A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Doseranging Trial of OPC-131461 in Cardiac Edema (Congestive Heart Failure [CHF])
Phase: PHASE2
Conditions: Cardiac Edema (CHF)
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-
ranging Trial of OPC-131461 for Cardiac Edema (Congestive Heart Failure) 
 
 
 
NCT Number: NCT05615363 
Protocol No. 351-102-00004  
Version Date: 27 Dec 2023  

 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
 
OPC-131461 
Translation of Japanese Original 
CLINICAL PROTOCOL AMENDMENT 
 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Dose-ranging Trial of OPC-131461 for Cardiac Edema (Congestive Heart Failure) 
 
A Dose-ranging Trial of OPC-131461 for Cardiac Edema (Congestive Heart Failure) 
 
Protocol No. 351-102-00004 
 
CONFIDENTIAL ⎯ PROPRIETARY INFORMATION 
 
Clinical Development Phase: 
2 
 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
Immediately Reportable Event  
Office of Pharmacovigilance Operations, 
Department of Pharmacovigilance 
Otsuka Pharmaceutical Co., Ltd. 
 
Email: IRE_351-102-00004@otsuka.jp 
 
Amendment 4 Approval: 
27 Dec 2023 
Amendment 3 Approval: 
15 Jun 2023 
Amendment 2 Approval: 
07 Mar 2023 
Amendment 1 Approval: 
31 Aug 2022 
Approval: 
14 Jun 2022 
 
 

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Table of Contents 
Table of Contents ........................................................................................... 2 
List of In-text Tables ..................................................................................... 9 
List of In-text Figures ..................................................................................10 
List of Abbreviations ...................................................................................11 
1 
Protocol Summary ..............................................................................14 
1.1 
Synopsis............................................................................................................ 14 
1.2 
Schema ............................................................................................................. 23 
1.3 
Schedule of Assessments.................................................................................. 24 
1.3.1 
Informed Consent .......................................................................................... 28 
1.3.2 
Screening ....................................................................................................... 28 
1.3.3 
Run-in Period (Day −3, Day −2, and Day −1) ............................................... 29 
1.3.4 
Randomization and Proceeding to the Treatment Period .............................. 30 
1.3.5 
Treatment Period (Day 1) .............................................................................. 31 
1.3.6 
Treatment Period (Day 2) .............................................................................. 32 
1.3.7 
Treatment Period (Day 3 and Day 4) ............................................................. 33 
1.3.8 
Treatment Period (Day 5) .............................................................................. 34 
1.3.9 
Treatment Period (Day 6) .............................................................................. 35 
1.3.10 
Treatment Period (Day 7) .............................................................................. 36 
1.3.11 
Treatment Period (Day 8) .............................................................................. 38 
1.3.12 
Treatment Period (Day 9 and Day 11) ........................................................... 39 
1.3.13 
Treatment Period (Day 10) ............................................................................ 40 
1.3.14 
Treatment Period (Day 12) ............................................................................ 41 
1.3.15 
Treatment Period (Day 13) ............................................................................ 42 
1.3.16 
Treatment Period (Day 14) ............................................................................ 42 
1.3.17 
Treatment Period (End of Treatment Examination on Day 15 or 
Withdrawal Examination: the Day after the Final IMP Administration) ...... 44 
1.3.18 
Post-treatment Observation Period (Post-treatment Examination on 
Day 16: 2 Days after the Final IMP Administration) .................................... 45 
1.3.19 
Follow-up Examination (Day 24 to Day 28: 10 to 14 Days after the 
Final IMP Administration) ............................................................................ 46 
2 
Introduction ........................................................................................48 

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2.1 
Trial Rationale .................................................................................................. 48 
2.2 
Background ...................................................................................................... 49 
2.2.1 
Nonclinical Data ............................................................................................ 50 
2.2.2 
Clinical Data .................................................................................................. 52 
2.3 
Known and Potential Risks and Benefits ......................................................... 56 
3 
Objectives and Endpoints ..................................................................58 
4 
Trial Design .........................................................................................59 
4.1 
Type/Design of Trial ........................................................................................ 59 
4.2 
Scientific Rationale for Trial Design................................................................ 60 
4.3 
Dosing Rationale .............................................................................................. 62 
4.4 
End of Trial Definition ..................................................................................... 63 
4.5 
Definition of Completed Subjects .................................................................... 63 
5 
Trial Population ..................................................................................64 
5.1 
Subject Selection and Numbering .................................................................... 64 
5.2 
Eligibility Criteria............................................................................................. 64 
5.2.1 
Inclusion Criteria ........................................................................................... 64 
5.2.1.1 
Screening Period ........................................................................................ 64 
5.2.1.2 
Run-in Period ............................................................................................. 66 
5.2.2 
Exclusion Criteria .......................................................................................... 66 
5.3 
Lifestyle Considerations ................................................................................... 68 
5.3.1 
Meals and Dietary Restrictions ...................................................................... 68 
5.3.2 
Caffeine, Alcohol, and Tobacco .................................................................... 68 
5.3.3 
Activity .......................................................................................................... 68 
5.4 
Screen Failures ................................................................................................. 68 
6 
Trial Treatments .................................................................................69 
6.1 
Trial Treatments Administered ........................................................................ 69 
6.1.1 
Medical Devices ............................................................................................ 70 
6.2 
Management of Investigational Medicinal Product ......................................... 70 
6.2.1 
Packaging and Labeling ................................................................................. 70 
6.2.2 
Storage ........................................................................................................... 70 
6.2.3 
Accountability ................................................................................................ 70 
6.2.4 
Returns and Destruction ................................................................................ 71 

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6.2.5 
Reporting of Product Quality Complaints ..................................................... 71 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints ................................ 71 
6.2.5.2 
Information Required for Purposes of Reporting Product Quality 
Complaints ................................................................................................. 72 
6.2.5.3 
Return Process When Product Quality Complaints Are Received ............ 72 
6.2.5.4 
Assessment/Evaluation .............................................................................. 72 
6.2.6 
Investigational Medicinal Product Reserve Sample Requirements ............... 72 
6.3 
Measures to Minimize/Avoid Bias ................................................................... 72 
6.4 
Subject Compliance .......................................................................................... 73 
6.5 
Concomitant Medications and Therapies ......................................................... 73 
6.5.1 
Prohibited Medications and Therapies .......................................................... 74 
6.5.2 
Medications Requiring Caution for Concomitant Use .................................. 75 
6.5.3 
Restricted Medications and Therapies ........................................................... 75 
6.5.4 
Rescue Medications ....................................................................................... 76 
6.6 
Intervention After the End of the Trial ............................................................. 76 
7 
Stopping Rules, Withdrawal Criteria, and Procedures ..................77 
7.1 
Entire Trial or Treatment .................................................................................. 77 
7.2 
Individual Site .................................................................................................. 77 
7.3 
Individual Subject Discontinuation .................................................................. 77 
7.3.1 
Treatment Interruption ................................................................................... 77 
7.3.2 
Treatment Discontinuation ............................................................................ 77 
7.3.3 
Documenting Reasons for Treatment Discontinuation .................................. 78 
7.3.4 
Withdrawal of Consent or Assent .................................................................. 79 
7.3.5 
Procedures to Encourage Continued Trial Participation ............................... 80 
7.4 
Definition of Subjects Lost to Follow-up ......................................................... 80 
8 
Trial Procedures .................................................................................81 
8.1 
Efficacy Assessments ....................................................................................... 81 
8.1.1 
Body Weight .................................................................................................. 81 
8.1.2 
Congestive Findings (Lower Limb Edema, Jugular Venous Distension, 
Hepatomegaly, Pulmonary Rales, and Cardiac Third Sound) ....................... 81 
8.1.3 
Chest X-ray (Cardiothoracic Ratio and Pulmonary Congestion) .................. 82 
8.1.4 
NYHA Functional Classification ................................................................... 83 
8.2 
Pharmacokinetic Assessments .......................................................................... 83 

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8.2.1 
Pharmacokinetic Blood/Plasma Samples ...................................................... 83 
8.3 
Pharmacodynamic Assessments ....................................................................... 85 
8.3.1 
Urine Volume ................................................................................................ 85 
8.3.1.1 
Urine Volume in a Time Point Set ............................................................. 85 
8.3.1.2 
Daily Urine Volume ................................................................................... 85 
8.3.2 
Fluid Intake .................................................................................................... 85 
8.3.3 
Fluid Balance ................................................................................................. 86 
8.3.4 
Clinical Laboratory Tests for Pharmacodynamic Assessments ..................... 86 
8.4 
Pharmacogenomic Assessments ....................................................................... 87 
8.5 
Exploratory Assessments ................................................................................. 87 
8.5.1 
Carbohydrate Antigen 125 (CA125) ............................................................. 87 
8.5.2 
Echocardiography for LVEF ......................................................................... 88 
8.6 
Future Biospecimen Research Samples ........................................................... 88 
8.6.1 
Scope of Future Biospecimen Research ........................................................ 89 
8.6.2 
Summary of Procedures for Future Biospecimen Research Samples ........... 90 
8.6.3 
Retention of Future Biospecimen Research Samples .................................... 90 
8.6.4 
Genomic/Genetic Analysis ............................................................................ 91 
8.6.5 
Biomarker Analysis ....................................................................................... 91 
8.6.6 
Informed Consent for Participation in Future Biospecimen Research 
and Withdrawal of Consent ........................................................................... 92 
8.6.7 
Disclosure of Analysis Results to Subjects ................................................... 92 
8.7 
Safety Assessments .......................................................................................... 92 
8.7.1 
Clinical Laboratory Assessments .................................................................. 92 
8.7.2 
Physical Examination .................................................................................... 93 
8.7.3 
Vital Signs ..................................................................................................... 94 
8.7.4 
Electrocardiography ....................................................................................... 94 
8.7.5 
Suicidality Monitoring ................................................................................... 95 
8.7.6 
Other Safety Variables ................................................................................... 95 
8.8 
Adverse Events ................................................................................................. 95 
8.8.1 
Definitions ..................................................................................................... 95 
8.8.2 
Eliciting and Reporting Adverse Events ........................................................ 97 
8.8.3 
Immediately Reportable Events ..................................................................... 98 
8.8.4 
Medical Device Incidents (Including Malfunctions) ..................................... 98 

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8.8.5 
Adverse Events of Special Interest ................................................................ 99 
8.8.6 
Potential Serious Hepatotoxicity ................................................................... 99 
8.8.7 
Procedure for Breaking the Blind .................................................................. 99 
8.8.8 
Follow-up of Adverse Events ........................................................................ 99 
8.8.8.1 
Follow-up of Nonserious Adverse Events ................................................. 99 
8.8.8.2 
Follow-up of Immediately Reportable Events ......................................... 100 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring after Last Scheduled Contact .................................................. 100 
8.9 
Treatment of Overdose ................................................................................... 101 
8.10 
Subject Assessment Recording ...................................................................... 101 
8.11 
Other Assessments ......................................................................................... 101 
9 
Statistical Considerations ................................................................101 
9.1 
Sample Size .................................................................................................... 101 
9.2 
Datasets for Analysis ...................................................................................... 101 
9.3 
Handling of Missing Data for Primary and Secondary Endpoint Analysis ... 102 
9.4 
Statistical Analyses......................................................................................... 102 
9.4.1 
Efficacy Analyses ........................................................................................ 102 
9.4.1.1 
Primary Efficacy Endpoint Analysis ........................................................ 102 
9.4.1.2 
Key Secondary Efficacy Endpoint Analysis ............................................ 102 
9.4.1.3 
Secondary Efficacy Endpoint Analysis .................................................... 102 
9.4.1.4 
Control of Experiment-wise Type 1 Error ............................................... 104 
9.4.1.5 
Other Efficacy Endpoint Analysis ........................................................... 104 
9.4.2 
Safety Analysis ............................................................................................ 104 
9.4.2.1 
Adverse Events......................................................................................... 104 
9.4.2.2 
Clinical Laboratory Data .......................................................................... 104 
9.4.2.3 
Physical Examination and Vital Signs Data............................................. 105 
9.4.2.4 
Electrocardiogram Data ........................................................................... 105 
9.4.2.5 
Other Safety Data ..................................................................................... 105 
9.4.3 
Other Analyses ............................................................................................. 105 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics .......................... 105 
9.4.3.2 
Pharmacokinetic Analysis ........................................................................ 105 
9.4.3.3 
Pharmacodynamic Analysis ..................................................................... 107 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis ......................................... 107 

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9.4.3.5 
Pharmacogenomic Analysis ..................................................................... 107 
9.4.3.6 
Exploratory Endpoint Analysis ................................................................ 107 
9.5 
Interim Analysis and Adaptive Design .......................................................... 108 
9.5.1 
Data Monitoring Committee ........................................................................ 108 
10 
Supporting Documentation and Operational Considerations .....109 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations .......... 109 
10.1.1 
Ethics and Responsibility ............................................................................ 109 
10.1.2 
Informed Consent ........................................................................................ 109 
10.1.3 
Confidentiality ............................................................................................. 110 
10.1.4 
Quality Control and Quality Assurance ....................................................... 110 
10.1.4.1 
Monitoring ............................................................................................... 110 
10.1.4.2 
Auditing ................................................................................................... 111 
10.1.5 
Protocol Deviations ..................................................................................... 111 
10.1.6 
Records Management .................................................................................. 111 
10.1.6.1 
Source Documents ................................................................................... 111 
10.1.6.2 
Data Collection......................................................................................... 112 
10.1.6.3 
File Management at the Trial Site ............................................................ 113 
10.1.6.4 
Records Retention at the Trial Site .......................................................... 113 
10.1.6.5 
Publication Authorship Requirements ..................................................... 113 
10.2 
Appendix 2: Clinical Laboratory Tests .......................................................... 115 
10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information ..................................................................................................... 116 
10.4 
Appendix 4: List of Prohibited Medications .................................................. 118 
10.5 
Allowability of Concomitant Use of Topical Agents among Prohibited 
Concomitant Medications............................................................................... 123 
10.5.1 
Conditions for Topical Agents in This Document ....................................... 123 
10.5.2 
Other Remarks for Topical Agents .............................................................. 123 
10.5.3 
Dosage Forms that May Fall under the Category of General Topical 
Agents (Excerpted from [3] Monographs for Preparations, General 
Rules for Preparations, the Japanese Pharmacopoeia, Seventeenth 
Edition) ........................................................................................................ 124 
10.6 
Appendix 6: List of Medications Requiring Caution for Concomitant Use... 126 
10.7 
Appendix 7: Protocol Amendments ............................................................... 133 
10.7.1 
Protocol Amendment(s)/Administrative Change(s) .................................... 134 

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10.7.1.1 
Protocol Amendment 1 ............................................................................ 134 
10.7.2 
Protocol Amendment 2 ................................................................................ 139 
10.7.3 
Protocol Amendment 3 ................................................................................ 148 
10.7.4 
Protocol Amendment 4 ................................................................................ 153 
11 
References ..........................................................................................161 
 
 

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List of In-text Tables 
Table 1.3-1 
Schedule of Assessments .............................................................. 24 
Table 1.3-2 
Allowable Time Windows for Postdose 
Examinations/Assessments ........................................................... 27 
Table 2.2.2-1 
Adverse Reactions Reported in more than 1 Subject in Any 
Treatment Group after Single Oral Administration of 
OPC-131461 Suspension at 5 to 320 mg ...................................... 54 
Table 2.2.2-2 
Adverse Reactions Reported in more than 1 Subject in Any 
Treatment Group after Repeated Oral Administration of 
OPC-131461 Suspension at 5, 40, and 100 mg ............................ 55 
Table 3-1 
Trial Objectives and Endpoints ..................................................... 58 
Table 6.1-1 
Dose and Drugs to Use for Each Treatment Group ...................... 70 
Table 6.5.1-1 
List of Prohibited Medications...................................................... 74 
Table 6.5.3-1 
Restricted Medications and Therapies .......................................... 76 
Table 8.1.2-1 
Criteria for Assessment of Lower Limb Edema ........................... 81 
Table 8.1.3-1 
Criteria for Assessment of Pulmonary Congestion ....................... 82 
Table 8.1.4-1 
NYHA Functional Classification .................................................. 83 
Table 8.3.4-1 
Pharmacodynamic Clinical Laboratory Assessments ................... 87 
Table 9.4-1 
Improvement Grading for Lower Limb Edema and 
Pulmonary Congestion ................................................................ 103 
Table 10.2-1 
Clinical Laboratory Assessments ................................................ 115 
Table 10.4-1 
Drugs, Foods, Beverages, and Supplements that May Inhibit 
CYP3A4 ...................................................................................... 118 
Table 10.4-2 
Drugs, Foods, Beverages, and Supplements that May Induce 
CYP3A4 ...................................................................................... 120 
Table 10.4-3 
Drugs that May Inhibit OATP1B1/3, MATE, OAT, or OCT ..... 121 
Table 10.4-4 
Drugs that May Induce OATP1B1/3, MATE, OAT, or OCT .... 122 
Table 10.4-5 
Drugs that Are CYP Substrates and that, When Used with 
OPC-131461, May or May Possibly Have Reduced Actions ..... 122 
Table 10.5.3-1 
Definitions of Topical Agents among Prohibited 
Concomitant Medications ........................................................... 124 
Table 10.6-1 
List of Medications Requiring Caution for Concomitant Use .... 126 
 
 
 

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List of In-text Figures 
Figure 1.2-1 
Trial Design Schematic ................................................................. 23 
 
 

 
 
 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APTT 
activated partial thromboplastintime 
AST 
aspartate aminotransferase 
AUC∞ 
area under the concentration-time curve from time zero to infinity 
AUCt 
area under the concentration-time curve calculated to the last 
observable concentration at time t 
AUC24h 
area under the concentration-time curve from time zero to 24 hours 
AUC24h/D 
AUC24h normalized by dose 
AVP 
arginine vasopressin 
BA 
bioavailability 
BCRP 
breast cancer resistance protein 
BMI 
body mass index 
BNP 
brain natriuretic peptide 
BSEP 
bile salt export pump 
CA125 
carbohydrate antigen 125 
cAMP 
cyclic adenosine 3',5'-monophosphate 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK (CPK) 
creatine kinase (creatine phosphokinase) 
CL/F 
apparent clearance of drug from plasma after extravascular 
administration 
CL/F/BW 
CL/F normalized in body weight 
Cmax 
maximum (peak) plasma concentration of the drug 
Cmax/D 
Cmax normalized by dose 
CRO 
contract research organization 
Ctrough 
trough drug concentration 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
eGFRcre 
estimated glomerular filtration rate using the creatinine 
eGFRcys 
estimated glomerular filtration rate using the cystatin C 
FBR 
future biospecimen research 
FOCBP 
females of childbearing potential 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
γ-GTP 
γ-glutamyl transpeptidase 
hCG 
human chorionic gonadotropin 

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Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
HMG-CoA 
β-hydroxy β-methylglutaryl-CoA 
IB 
investigator’s brochure 
IC50 
concentration of drug producing 50% inhibition 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRE 
immediately reportable event 
IUD 
intrauterine device 
IWRS 
interactive web response system 
Ki 
inhibition constant 
LDH 
lactate (lactic acid) dehydrogenase 
LOCF 
last observation carried forward 
LVEDV 
left ventricular end-diastolic volume 
LVEF 
left ventricular ejection fraction 
LVESV 
left ventricular end-systolic volume 
λz 
apparent terminal-phase disposition rate constant (first-order) 
MATE 
multidrug and toxin extrusion 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
PD 
pharmacodynamic 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic 
PQC 
product quality complaint 
PT-INR 
prothrombin time international normalized ratio 
QTc 
corrected QT interval 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R(AUC24h) 
accumulation ratio of multiple dose to first dose at regular 
administration for AUC24h 
R(Cmax) 
accumulation ratio of multiple dose to first dose at regular 
administration for Cmax 
R(Ctrough) 
accumulation ratio of multiple dose to first dose at regular 
administration for Ctrough 
SAE 
serious adverse event 
SGLT2 
sodium-glucose cotransporter 2 
t1/2,z 
terminal-phase elimination half life 

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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum plasma concentration 
tlast 
time of last measurable (positive) concentration 
UGT 
uridine diphosphate glucuronosyltransferase 
 

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1 
Protocol Summary 
1.1 
Synopsis 
Name of Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
Name of Investigational Medicinal Product: 
OPC-131461 
 
Protocol No.: 
351-102-00004 
 
Protocol Title: 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-
ranging Trial of OPC-131461 in Cardiac Edema (Congestive Heart Failure [CHF]) 
 
Protocol Lay Person Short Title: 
A Dose-ranging Trial of OPC-131461 in Cardiac Edema (CHF) 
 
Clinical Phase/Trial Type: 
Phase 2/dose-ranging 
 
Treatment/Indication: 
Patients with CHF with volume overload despite having received diuretics other than 
vasopressin antagonists 
 

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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary Objectives: 
To investigate the dose response in respect of 
weight decrease following repeated oral 
administration of OPC-131461 at 1, 2, 5, and 
10 mg or placebo in patients with CHF with 
volume overload despite having received diuretics 
other than vasopressin antagonists 
Primary Efficacy Endpoint: 
Change in body weight from baseline to last 
assessment time point (the day after investigational 
medicinal product [IMP] administration) by Day 8 
 
Secondary Efficacy Endpoints: 
Change in body weight from baseline to last 
assessment time point (the day after IMP 
administration) by Day 15 
 
Percent change in body weight from baseline to 
last assessment time point (the day after IMP 
administration) by Day 8 
 
Percent change in body weight from baseline to 
last assessment time point (the day after IMP 
administration) by Day 15 
 
Improvement of or change in congestive findings 
(lower limb edema, pulmonary congestion, jugular 
venous distension, hepatomegaly, cardiothoracic 
ratio, pulmonary rales, and cardiac third sound) 
from baseline to last assessment time point (the 
day of IMP administration) by Day 7 
 
Improvement of or change in congestive findings 
(lower limb edema, pulmonary congestion, jugular 
venous distension, hepatomegaly, cardiothoracic 
ratio, pulmonary rales, and cardiac third sound) 
from baseline to last assessment time point (the 
day after IMP administration) by Day 15 
 
Congestive findings (lower limb edema, 
pulmonary congestion, jugular venous distension, 
hepatomegaly, cardiothoracic ratio, pulmonary 
rales, and cardiac third sound), time to resolution 
of congestive findings, and the New York Heart 
Association (NYHA) Functional Classification 
Secondary Objectives: 
To confirm the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics of 
OPC-131461 versus placebo in patients with CHF 
with volume overload despite having received 
diuretics other than vasopressin antagonists 
Safety: 
Adverse events (AEs), clinical laboratory test 
values, physical examination findings, vital signs, 
and 12-lead electrocardiogram (ECG) 
 
Pharmacodynamic endpoint: 
Serum osmolality, serum electrolyte (sodium, 
potassium) concentrations, serum troponin I 
concentration, serum N-terminal pro-brain 
natriuretic peptide (NT-proBNP) concentration, 
serum creatinine concentration, serum cystatin C 
concentration, estimated glomerular filtration rate 
(estimated glomerular filtration rate using the 
creatinine [eGFRcre], estimated glomerular 
filtration rate using the cystatin C [eGFRcys]), 

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Objectives 
Endpoints 
plasma arginine vasopressin (AVP) concentration, 
plasma brain natriuretic peptide (BNP) 
concentration, plasma renin activity, and plasma 
aldosterone concentration 
 
Daily urine volume/fluid intake/fluid balance 
Urine volume/fluid intake/fluid balance in a time 
point set 
Urine volume/fluid intake/fluid balance per hour 
Urine osmolality, urine sodium excretion, urine 
potassium excretion, urine aquaporin 2 
concentration, and free water clearance 
 
Pharmacokinetic endpoint: 
Plasma concentrations and PK parameters of 
OPC-131461 and its metabolites 
Exploratory Objective: 
To conduct an exploratory investigation of OPC-
131461 compared to placebo. 
Exploratory endpoint: 
Carbohydrate antigen 125 (CA125), 
echocardiography for left ventricular ejection 
fraction (LVEF) 
 
Trial Design: 
Multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging 
trial 
 
Trial Population: 
Total of 155 Japanese male and female subjects (31 subjects each in 5 groups; the target 
number of subjects who begin trial treatment), between ages of 18 and 89 years, 
inclusive, at the time of informed consent, with CHF with volume overload (lower limb 
edema, pulmonary congestion, or jugular venous distension) despite having received 
diuretics other than vasopressin antagonists 
 

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Key Inclusion/Exclusion Criteria: 
Inclusion Criteria 
Screening Period 
Subjects who meet all of the following inclusion criteria (screening period) will be 
selected. 
1) 
Subjects with CHF with any of lower limb edema, pulmonary congestion, or jugular venous 
distension due to volume overload. Subjects with pulmonary congestion confirmed by a chest X-ray 
taken within 14 days before informed consent may be included. 
2) 
Subjects undergoing any of the following diuretic therapies (including subjects scheduled to begin 
such therapy during the run-in period) 
• 
Loop diuretics at a dosage equivalent to 40 mg/day or more of furosemide tablet/fine granule 
• 
Concomitant administration of a loop diuretic and a thiazide diuretic (including similar drugs) 
at any doses 
• 
Concomitant administration of a loop diuretic and a mineralocorticoid receptor antagonist or 
potassium-sparing diuretic at any doses 
Note: The type and dosages of concomitant diuretics are specified as follows: 
a) Loop diuretics at a dosage equivalent to 40 mg/day or more of furosemide tablet/fine 
granule 
Bumetanide tablet, 1 mg; azosemide tablet, 60 mg; and torasemide tablet, 8 mg 
b) Thiazide diuretics (including similar drugs) 
Hydrochlorothiazide tablet, trichlormethiazide tablet, benzylhydrochlorothiazide tablet, 
and mefruside tablet 
c) Mineralocorticoid receptor antagonists or potassium-sparing diuretics 
Spironolactone tablet/fine granule and triamterene capsules 
3) 
Males or females between the ages of 18 and 89 years inclusive (at the time of informed consent) 
4) 
Subjects who were currently hospitalized or who are able to be hospitalized from the day before the 
run-in period (Day −4) until the end of the post-treatment examination (Day 16) 
5) 
Subjects who are able to take oral medications 
6) 
Subjects capable of providing written informed consent prior to the initiation of any trial-related 
procedures and capable, in the opinion of the investigator or subinvestigator, of complying with all 
the requirements of the trial. 
 
Run-in Period 
Subjects who meet all of the following inclusion criteria (run-in period) will proceed to 
the treatment period. 
7) 
Subjects with lower limb edema, jugular venous distension (on Day −1 in the run-in period), or 
pulmonary congestion (by chest X-ray in the run-in period) 
8) 
Subjects who received diuretics without any change in the dose or regimen during the run-in period 
9) 
Subjects whose body weight changed by no more than 1.0 kg in 2 days before trial treatment begins 
(ie, between Day −2 and Day −1 in the run-in period) 
 

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Exclusion Criteria 
Subjects who meet any of the following exclusion criteria in the screening period will be 
excluded. 
1) 
Subjects with acute heart failure 
2) 
Subjects with an assisted circulation device 
3) 
Subjects with any of the following diseases, complications, or symptoms: 
• 
Suspected decrease in the circulating blood volume 
• 
Hypertrophic cardiomyopathy (other than the dilated phase) 
• 
Cardiac valve disease with significant valve stenosis 
• 
Hepatic encephalopathy with difficulty in adequate hydration 
4) 
Subjects with acute myocardial infarction occurred within 30 days before screening examination 
5) 
Subjects with confirmed active myocarditis or amyloid cardiomyopathy 
6) 
Subjects with any of the following diseases, complications, or symptoms: 
• 
Uncontrolled diabetes mellitus 
• 
Anuria 
• 
Urinary excretion disorders due to urinary stenosis, urinary calculus, tumor 
7) 
Subjects with any of the following medical histories: 
• 
Occurrence of sustained ventricular tachycardia or ventricular fibrillation within 30 days prior 
to screening examination in subjects not using an implantable cardioverter defibrillator 
• 
Occurrence of a cerebrovascular disorder within 6 months prior to screening examination 
(excluding asymptomatic cerebral infarction) 
• 
History of hypersensitivity or idiosyncratic reaction to benzazepines (tolvaptan sodium 
phosphate, tolvaptan, mozavaptan hydrochloride, and benazepril hydrochloride) 
8) 
Subjects who have undergone surgical gastrectomy or small intestine resection 
9) 
Morbidly obese subjects with the body mass index (BMI = body weight [kg] / height [m]2) of more 
than 35 kg/m2 
10) Subjects with supine systolic blood pressure of less than 90 mmHg 
11) Subjects with any of the following clinical laboratory abnormalities: 
• 
Total bilirubin > 3.0 mg/dL 
• 
Serum creatinine > 3.0 mg/dL 
• 
Serum sodium < 125 mEq/L, serum sodium > 147 mEq/L 
• 
Serum potassium > 5.5 mEq/L 
12) Subjects with prior or concurrent hepatic impairment (including subjects with aspartate 
aminotransferase [AST] or alanine aminotransferase [ALT] greater than 3 times the upper limit of 
reference range at screening examination) 
13) (Removed due to deletion in Protocol Amendment 3)  
14) Subjects who cannot sense thirst or who have difficulty in ingesting water 
15) Females who are breastfeeding or have a positive pregnancy test before trial treatment begins 
16) Sexually active males of reproductive potential or sexually active females of childbearing potential 
who do not agree to practice 2 different methods of birth control or remain fully abstinent during 
the trial and for 90 days (males) or for 180 days (females) after the final administration of IMP. If 
employing birth control, 2 of the following methods must be used: vasectomy, tubal ligation, 
intrauterine device (IUD), birth control pill, and condom (all of these methods are approved or 
certified in Japan) 

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17) Subjects who used any of the following drugs/foods/beverages/supplements at and after the 
specified time point 
 
Drug, Food, Beverage, Supplement 
Timing 
Vasopressin antagonists 
28 days before screening examination 
Drugs, foods, beverages, and supplements that may 
inhibit cytochrome P450 (CYP) 3A4 (see 
Table 10.4-1). 
However, topical agents that are allowed in 
Section 10.5 are excluded. 
4 days before IMP administration 
Drugs, foods, beverages, and supplements that may 
induce CYP3A4 (see Table 10.4-2). 
However, topical agents that are allowed in 
Section 10.5 are excluded. 
8 days before IMP administration 
Drugs that may inhibit or induce OATP1B1/3, 
MATE, OAT, or OCT (see Table 10.4-3 and 
Table 10.4-4). 
However, topical agents that are allowed in 
Section 10.5 are excluded. 
14 days before IMP administration 
Drugs that are CYP substrates and that, when used 
with OPC-131461, may or may possibly have 
reduced action (see Table 10.4-5). 
However, topical agents that are allowed in 
Section 10.5 are excluded. 
4 days before IMP administration 
Ensitrelvir 
11 days before IMP administration 
Drugs that are not approved in Japan, including 
IMPs other than OPC-131461 
30 days or 5 times the half-life of the 
drug, whichever is longer, before 
screening examination 
18) Subjects who, in the opinion of the investigator or subinvestigator, are inappropriate for inclusion 
in the trial for any other reason 
 
Trial Site(s): 
Approximately 60 sites in Japan 
 
Investigational Medicinal Product(s), Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration: 
[Investigational Medicinal Products] 
• OPC-131461 tablet 1 mg 
• OPC-131461 tablet 5 mg 
• Placebo tablet 
 
[Dose, Dosage Regimen, and Treatment Duration] 
• Dosage regimen: once-daily oral administration 
• Dose: 1, 2, 5, or 10 mg/day or 0 mg of OPC-131461 

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• Treatment duration: 14 days (However, the treatment will be terminated before 
completing 14 days of treatment, if the investigator or subinvestigator judges that no 
further improvement of volume overload is necessary in a case that any of congestive 
findings [lower limb edema, pulmonary congestion, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound] were resolved or in other 
cases.) 
 
The investigator or subinvestigator will orally administer to subjects 2 tablets of either 
the OPC-131461 tablet at 1 or 5 mg or the placebo tablet with water once daily for 
14 days immediately after urination for urine volume measurement following breakfast. 
From Day 2 onward, IMP administration should take place at the clock time within 
± 20 minutes of the dosing time on Day 1. Subjects who did not have any breakfast on a 
day of administration will also receive the IMP. 
 
Trial Assessments: 
Assessments for Efficacy: 
Body weight, assessment of congestive findings (lower limb edema, jugular venous 
distension, hepatomegaly, pulmonary rales, and cardiac third sound), chest X-ray 
(cardiothoracic ratio and pulmonary congestion), and assessment of NYHA Functional 
Classification 
 
Assessments for Safety: 
AEs, clinical laboratory tests (hematology, biochemistry, coagulation test, and 
urinalysis), physical examination, vital signs (blood pressure, pulse rate, and 
temperature), and 12-lead ECG 
 
Assessments for Pharmacodynamics: 
• Blood sampling for assessment of serum osmolality, serum electrolyte (sodium, 
potassium) concentrations, serum cystatin C concentration, serum creatinine 
concentration, AVP concentration, plasma renin activity, plasma aldosterone 
concentration, plasma BNP concentration, serum troponin I concentration, and serum 
NT-proBNP concentration 
• Measurement of daily or sectional urine volume/fluid intake 
• Urine collection for assessment of urine osmolality, urine sodium excretion, urine 
potassium excretion, and urine aquaporin 2 concentration 

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Assessments for Pharmacokinetics: 
Blood sampling for assessment of plasma concentrations and PK parameters of 
OPC-131461 and its metabolites 
 
Exploratory Assessment: 
Blood sampling for assessment of CA125 and echocardiography for LVEF 
 
Screening/Other: 
Subject demographics including complications and medical history, urine pregnancy test 
(only for female subjects of childbearing potential), serum pregnancy test (only for 
female subjects with a positive urine pregnancy test), deoxyribonucleic acid (DNA) 
storage (optional), and storage of biomarker samples (optional) 
 
Data Monitoring Committee: 
None 
 
Statistical Methods: 
The primary endpoint is the change in body weight from baseline (before IMP 
administration on Day 1) to last assessment time point (the day after IMP administration) 
by Day 8. 
The primary analysis will use an analysis of covariance model with treatment group as a 
fixed effect and baseline body weight as a covariate. Each OPC-131461 dose group will 
be compared with the placebo group at a two-sided significance level of 5%, and the 
difference in the least squares mean between the treatment groups and the two-sided 95% 
confidence interval will be determined. 
The necessary sample size is set as 31 subjects per group. 
Assuming that a dose of OPC-131461 5 mg or higher is equivalent to that of tolvaptan 
15 mg in patients with CHF, the sample size required to demonstrate the superiority of 
OPC-131461 over placebo in terms of the primary endpoint, ie, the change in body 
weight from baseline to the last assessment time point (the day after IMP administration) 

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by Day 8, was determined (multiplicity relating to the use of more than one OPC-131461 
dose group was not considered). 
The results of the phase 3 confirmatory trial of tolvaptan (Protocol 156-06-002; placebo-
controlled 7-day treatment) demonstrated that the change from baseline in body weight 
on the day after the final IMP administration (LOCF) was −0.45 ± 0.93 kg 
(mean ± standard deviation [hereinafter, the same applies]) for the placebo group and 
−1.54 ± 1.61 kg for the tolvaptan 15-mg group. Based on these results, assuming a 
treatment difference of −1.09, standard deviation (combined) of 1.30, statistical power of 
90%, and two-sided significance level of 5%, the sample size required is set as 
31 subjects per group for a total of 155 subjects. 
 
Trial Duration: 
Each subject in this trial is expected to participate in the following periods of the trial: 
• Screening period: a maximum of 4 days 
• Run-in period: 3 days 
• Treatment period: 15 days (14 days of trial treatment + 1 day of end-of-treatment 
[EOT] examination) 
• Post-treatment observation period: 1 day 
• Follow-up period: a maximum of 12 days 
 
Overall, the trial duration is from signing of the first informed consent form to the final 
subject assessment is expected to be approximately 21 months. 
All subjects should undergo EOT/withdrawal examination, post-treatment observation, 
and follow-up after the final IMP administration even if the actual treatment duration is 
less than 14 days as specified in the protocol. 
 

 
 
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1.2 
Schema 
 
Figure 1.2-1 
Trial Design Schematic 
-3
-2
-1
15
(Day)
Post-
treatment
Observation
Period
Follow-up Period
(3 days)
(15 days)
(2 days after
the final IMP
administration)
(10-14 days after
the final IMP
administration)
OPC-131461 5-mg group
OPC-131461 10-mg group
Screening
Period
Run-in
Period
Treatment Period
Hospitalization (for 20 days from Day −4 to Day 16)
Inpatient or
outpatient
period
Placebo group
-7 to -4
1 to 14
16
24 to 28
Diuretics: fixed dose and regimen
Informed consent (the day of trial initiation)
EOT examination (the day after the final
IMP administration)
Post-treatment observation
(the day of post-treatment observation)
Post-treatment follow-up
(Final observation on the day of trial
completion)
OPC-131461 1-mg group
OPC-131461 2-mg group
R

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1.3 
Schedule of Assessments 
Table 1.3-1 
Schedule of Assessments 
 
Period (Day)
Post-treatment
Observation
Period
Follow-up
Period
EOT
Examination
(Withdrawal
Examination)
Post-treatment
Observation
Follow-up
Examination
−7 to −4
−4
−3
−2
−1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
24 to 28
Item
Day after the
final IMP
administration
2 days after the
final IMP
administration
10 to 14 days
after the final
IMP
administration
Hospitalization
Informed consent
◆
Informed consent for optional programs
Demographics
◆
Inclusion/exclusion criteria
◆
◆
Subject enrollment and randomizationa
◆
●
◆
IMP administration
◎
◎
◎
◎
◎
◎
◎
◎
◎
◎
◎
◎
◎
◎
Check on concomitant diuretics
Plasma drug concentration
■
■
■
■
■
■
■b,c
■b,d
◆d
■
■
■
■
■f
Serum electrolyte (sodium, potassium ) concentrationsg,
serum osmolality
◆
■
■
■
■
■
■
■
■
■
■
■
●
●
●
Pharmacodynamic laboratory tests (serum, plasma)h
●
●
●
CA125
●
●
●
●
Clinical laboratory tests
◆
●
●
●
●
●
Body weight
◆
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Congestive findingsi
◆
◆
◆
◆
▼
▼
▼
▼
▼
▼
▼
▼
▼
▼
▼
▼
▼
▼
◆
◆
◆
Chest X-rayj
(cardiothoracic ratio, pulmonary congestion)
Physical examination
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
◆
Vital Signs
(blood pressure, pulse rate, body temperature)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
◆
Once in the run-in period
Once in the run-in period
◆
●
●
●
●
▼
◆
NYHA Functional Classification
Treatment Period
〇 (optional participation)
◆
◆
▼
◆
Screening Period
Run-in Period
Urine volume, fluid intake
Urine sodium and potassium concentrations, urine
osmolality, urine aquaporin 2 concentratione

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EOT = end-of-treatment. 
●, Before breakfast and before IMP administration (before breakfast on non-dosing days); , After breakfast; ■, At the specified time point (see Table 1.3-2); 
◆, At a feasible time; ▼, At a feasible time after IMP administration; ○, Optional program; □, Optional program (at the specified time point; see Table 1.3-2) 
Optional programs will be conducted only in subjects from whom optional informed consent was obtained at trial sites that agreed to store DNA and/or 
biomarker samples. 
Items that are not permitted to measure at hospitals during the trial period (See Section 6.3): Serum osmolality, plasma AVP concentration, urine osmolality, 
urine sodium concentration, urine potassium concentration, and urine aquaporin 2 concentration 
aSubject enrollment and randomization: 
The interactive web response system (IWRS) will be used to enroll subjects at the time of informed consent and to randomize them on Day 1. Subjects who 
meet all of the inclusion criteria and do not fall under any of the exclusion criteria will be randomized to the IMP. Randomization will take place on Day 1 
in principle (in the event of absolute necessity only, the subject may be randomized on Day −1, and in that case, the investigator or subinvestigator must 
reconfirm on Day 1 that the subject meets the inclusion criteria related to concomitant diuretics). Information on IMP administration and trial completion or 
discontinuation (at completion/discontinuation) will be entered via IWRS. 
bFor subjects who complete the trial early, blood sampling for plasma drug concentration measurement scheduled at the EOT examination and post-treatment 
examination will be conducted within the specified allowable time windows (see Table 1.3-2) with the time of the final IMP administration as a starting 
point. 
cFor subjects who discontinue the trial, blood sampling for plasma drug concentration measurement will be conducted at one feasible time point on the day of 
withdrawal examination. 
Period (Day)
Post-treatment
Observation
Period
Follow-up
Period
EOT
Examination
(Withdrawal
Examination)
Post-treatment
Observation
Follow-up
Examination
−7 to −4
−4
−3
−2
−1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
24 to 28
Item
Day after the
final IMP
administration
2 days after the
final IMP
administration
10 to 14 days
after the final
IMP
administration
12-Lead ECG (central)k
◆
■
▼
◆
◆
◆
Echocardiographyl
Urine pregnancy test (only for female subjects of
childbearing potential)
◆
◆
DNA storagem
〇
Storage of biomarker samples (plasma and urine)n
□
□
Check on concomitant medications/therapies
Adverse events
◆
Once in the run-in period
◆
Once by 2 days after the final IMP
administration
◆
Once in the run-in period
◆
Treatment Period
Screening Period
Run-in Period

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dFor subjects who discontinue the trial, blood sampling for plasma drug concentration measurement is not necessary. 
eUrine aquaporin 2 concentration will be measured on Day −1 and Day 14 (or the final IMP administration day). 
fFor subjects who complete the trial early and those who discontinue the trial, measurement of urine volume and fluid intake at the specified time points is not 
necessary; only daily urine volume and fluid intake will be measured. 
gSerum sodium and potassium concentrations will be measured at the central laboratory during the screening period, post-treatment observation period, and 
follow-up period, and will be measured not only at the central laboratory but also at the trial site during the treatment period. 
hSerum cystatin C concentration, serum creatinine concentration, plasma AVP concentration, plasma renin activity, plasma aldosterone concentration, plasma 
BNP concentration, serum troponin I concentration, and serum NT-proBNP concentration 
iCongestive findings: Lower limb edema, jugular venous distension, hepatomegaly, pulmonary rales, and cardiac third sound 
jChest X-ray: Cardiothoracic ratio and pulmonary congestion 
Only pulmonary congestion will be assessed at screening. For subjects who underwent chest X-ray at clinical examination before participating in the trial, 
chest X-ray may be omitted at screening examination and instead the X-ray images obtained at the pre-trial examination (within 14 days before informed 
consent) will be used in assessment. 
k12-lead ECG will be performed at a predose time and 2 to 4 hours postdose on Day 1, at a feasible postdose time on Day 7, and at a feasible time on other 
days. If a local measurement of serum potassium concentration is found to exceed 5.5 mEq/L on any day in the treatment period when 12-lead ECG is not 
scheduled in the protocol, then an additional 12-lead ECG will be performed as an unscheduled examination. 
lEchocardiography for left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and LVEF will be performed using the 
disc method (modified Simpson method). 
mDNA storage: Informed consent will be obtained before blood sampling for DNA storage. The blood sample will be collected before IMP administration on 
the day of initial administration (Day 1) in principle. If the blood sample is not collected at the specified time point or needs to be recollected, the blood 
sample will be collected at a feasible time during the trial. 
nStorage of biomarker samples: Informed consent will be obtained before blood and urine collections. Part of the urine sample will be used in a quantitative 
test of protein (before IMP administration on Day 1, the result of a qualitative test of protein performed as a part of clinical laboratory tests will be used). 
 

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Table 1.3-2 
Allowable Time Windows for Postdose Examinations/Assessments 
 
aAny allowable window will not be applied to the starting time points of 0 hours after breakfast and 0 hours postdose. 
 
Item
Allowable Window
Predose and before breakfast
Within 2 h predose
2, 4, 6, and 8 h postdose
Specified time ± 20 min
Day 2
24 h after Day 1 dosing (predose and before breakfast on Day 2)
Specified time −2 h and predose
24 h  after Day 6 or Day 13 dosing (predose and before breakfast on Day 7 or
Day 14)
Specified time −2 h and predose
2, 4, 6, and 8 h postdose
Specified time ± 20 min
Day 8
24 h after Day 7 dosing (predose and before breakfast on Day 8)
Specified time −2 h and predose
Day 12
24 h after Day 11 dosing (predose and before breakfast on Day 12)
Specified time −2 h and predose
Day 15 (EOT examination)
24 h after Day 14 dosing (or final IMP administration*) (before breakfast)
Specified time −2 h
Day 15 (EOT examination)
32 h after Day 14 dosing (or final IMP administration*)
Specified time ± 90 min
Day 16 (post-treatment examination)
48 h after Day 14 dosing (or final IMP administration*)
Specified time ± 2 h
Predose and before breakfast
Within 2 h predose
4-6 h postdose
–
8-12 h postdose
–
Day 2, Day 3, Day 4, Day 5, Day 6,
Day 8, Day 10, Day 12, and Day 14
Predose and before breakfast
Within 2 h predose
Day 2
8 h after Day 2 dosing
Specified time ± 1 h
Day 1
Predose and before breakfast
Within 2 h predose
Day 1 and Day 7
4 h postdose
Specified time  ± 30 min
Predose
After wake-up and before dosing
2-4 h postdose
–
Day −1
0-4, 4-8, 8-12, and 12-24 h after breakfast
Day 1, Day 7, and Day 14
0-4, 4-8, 8-12, and 12-24 h postdose
Day 15 (EOT examination)
24-28, 28-32, 32-36, and 36-48 h after Day 14 dosing
± 30 mina
Biomarker sample storage (plasma, urine)
12-Lead ECG (central)
Day 1
Urine volume/fluid intake/fluid balance in a
time point set
Time Point
Plasma drug concentration
(* for early completers)
Day 1
Day 7 and Day 14
Serum electrolyte (sodium, potassium)
concentrations, serum osmolality
Day 1 and Day 7

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Detailed procedures for the following visits shown in Table 1.3-1 are indicated. 
Examinations/assessments will be conducted and recorded as specified in Section 8.1, 
Section 8.2, Section 8.3, Section 8.4, Section 8.5, Section 8.6, Section 8.7, and 
Section 8.8. 
1.3.1 
Informed Consent 
Informed consent will be voluntary obtained from all subjects. See Section 10.1.2. 
The date of informed consent will be documented in the electronic case report form 
(eCRF). 
1.3.2 
Screening 
After acquisition of a subject’s informed consent, the investigator or subinvestigator will 
assign a unique subject identifier (ID) number to the subject in accordance with 
Section 5.1. The date of informed consent and the subject ID number will be recorded in 
the source documents and eCRF, and the subject will be entered in the IWRS. The IWRS 
operations will be specified in a separate written procedure, as a system for controlling 
the enrollment status of subjects. 
After acquisition of a subject’s informed consent, the following investigations and 
examinations will be performed as a screening examination within 7 to 4 days before the 
start of treatment (Day −7 to Day −4) to determine the subject’s eligibility for the trial. 
The results of eligibility assessment will be recorded in the source documents and eCRF. 
[Examination and Investigation Items] 
• Demographics (date of investigation, date of birth, sex, country in which the trial 
is being conducted, race, ethnicity, name of underlying disease, type of heart 
failure, presence/absence and type of arrhythmia, presence/absence of a 
pacemaker, presence/absence of an implantable cardioverter defibrillator, 
complications, classification of the complications, medical history [within the past 
5 years prior to informed consent]), and classification of the disease underlying 
CHF 
• Results of the eligibility assessment 
• Serum electrolyte (sodium, potassium) concentrations, and serum osmolality 
• Height (measured to one decimal place in cm; heights measured to more than one 
decimal place will be rounded to one decimal place.) 
• Body weight 
• BMI (Formula: BMI = body weight [kg] / height [m]2. BMI will be calculated 
based on the height and body weight at screening. The first decimal place will be 
rounded up.) 

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• Congestive findings (lower limb edema, jugular venous distension, hepatomegaly, 
pulmonary rales, and cardiac third sound) 
• Chest X-ray Note) (pulmonary congestion) 
• Clinical laboratory tests 
• Physical examination 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
• 12-Lead ECG (central) 
• Check on concomitant medications/therapies 
• Adverse events 
• Presence/absence of the childbearing potential 
• Urine pregnancy test (only for female subjects of childbearing potential; if the test 
result is positive, a serum pregnancy test will be performed.) 
Note) If a chest X-ray was performed in a medical examination before trial participation, 
the state of pulmonary congestion may be evaluated based on the image obtained in that 
medical examination (within 14 days prior to informed consent), rather than performing a 
chest X-ray during the screening examination. 
1.3.3 
Run-in Period (Day −3, Day −2, and Day −1) 
The investigator or subinvestigator will perform the following examinations and 
investigations to determine whether to proceed to the treatment period. Regardless of the 
usage of diuretics before the run-in period, the dose and dosage regimen of diuretic 
treatment at the start of the run-in period (Day −3) should not be changed until the end of 
the post-treatment examination. Hospitalization information will be recorded in the 
eCRF. 
1) Before Breakfast 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast, and measurement 
of urine volume and fluid intake will be started to evaluate the items shown 
below. On Day −1, urine volume in a time point set, fluid intake in a time point 
set, and fluid balance in a time point set (at the times specified in Table 1.3-2) will 
also be evaluated. 
• Daily urine volume, daily fluid intake, and daily fluid balance (difference 
between daily fluid intake and daily urine volume) 

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• Urine volume in a time point set, fluid intake in a time point set, and fluid 
balance in a time point set (at the times specified in Table 1.3-2) (on Day −1 
only) 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations (on Day −3 and Day −2) 
• Urine osmolality in a time point set, urine electrolyte (sodium, potassium) 
concentrations in a time point set, and urine aquaporin 2 concentration in a 
time point set (on Day −1 only) 
 
3) At a Feasible Time on Each Evaluation Day 
• Check on the use of concomitant diuretics 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
• Physical examination 
• Check on concomitant medications/therapies 
• Adverse events 
• Chest X-ray (cardiothoracic ratio and pulmonary congestion) (once during the 
run-in period) 
• NYHA Functional Classification (once during the run-in period) 
• 12-Lead ECG (central) (once during the run-in period) 
• Echocardiography (disc method [modified Simpson method]) (LVEDV, 
LVESV, and LVEF) (once during the run-in period) 
 
1.3.4 
Randomization and Proceeding to the Treatment Period 
1) Determination of Whether to Proceed to the Treatment Period 
The investigator or subinvestigator will evaluate the use of concomitant diuretics, 
body weight, and congestive findings during the run-in period, confirm that all of 
the inclusion criteria (run-in period) are met, and enter the confirmation results in 
the IWRS. The results of eligibility assessment will be recorded in the source 
documents and eCRF. 
 
2) Assignment of IMP Treatment to Subjects 
Subjects who meet all of the inclusion criteria (run-in period) will be randomized 
to one of the 5 groups shown below to receive the IMP in a double-blind manner. 
In principle, assignment will be performed on Day 1 (Assignment on Day  −1 is 
acceptable if unavoidable. When assignment is performed on Day −1, it should be 
reconfirmed on Day 1 that the inclusion criteria for concomitant diuretics are 
met). The investigator or subinvestigator will check the randomization number 
assigned in the IWRS. The date of randomization, randomization number, and 
IMP number will be recorded in the eCRF. 

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• OPC-131461 1-mg group 
• OPC-131461 2-mg group 
• OPC-131461 5-mg group 
• OPC-131461 10-mg group 
• Placebo group 
 
1.3.5 
Treatment Period (Day 1) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 
1) Before Breakfast and IMP Administration 
• Plasma drug concentration (at the time specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• Pharmacodynamic laboratory tests (serum cystatin C concentration, serum 
creatinine concentration, plasma AVP concentration, plasma renin activity, 
plasma aldosterone concentration, plasma BNP concentration, serum troponin 
I concentration, and serum NT-proBNP concentration) 
• CA125 
• Clinical laboratory tests 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
• Blood sampling and urine collection for storage of biomarker samples 
(optional) (at the time specified in Table 1.3-2) 
 
2) Before IMP Administration 
• 12-Lead ECG (central) (at the time specified in Table 1.3-2) 
• Blood sampling for DNA storage (optional) 
 
3) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Urine volume in a time point set, fluid intake in a time point set, and fluid 
balance in a time point set (at the times specified in Table 1.3-2) 
• Urine osmolality in a time point set and urine electrolyte (sodium, potassium) 
concentrations in a time point set 

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4) IMP Administration 
After confirming that a subject meets all of the inclusion criteria and do not fall 
under any of the exclusion criteria, the investigator or subinvestigator will instruct 
the subject to take the IMP. The investigator or subinvestigator will confirm that 
the subject has taken the IMP completely, and record the date and time of 
administration and the dose in the source documents and eCRF. 
• Status of IMP administration 
 
5) After IMP Administration 
• Plasma drug concentration (at the time specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• 12-Lead ECG (central) (at the time specified in Table 1.3-2) 
• Blood sampling and urine collection for storage of biomarker samples 
(optional) (at the time specified in Table 1.3-2) 
• Urine volume in a time point set, fluid intake in a time point set, and fluid 
balance in a time point set (at the times specified in Table 1.3-2) 
• Urine osmolality in a time point set and urine electrolyte (sodium, potassium) 
concentrations in a time point set 
 
6) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 
7) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 
1.3.6 
Treatment Period (Day 2) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 
1) Before Breakfast and IMP Administration 
• Plasma drug concentration (at the time specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 

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• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) After IMP Administration 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
 
5) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 
6) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 
1.3.7 
Treatment Period (Day 3 and Day 4) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 

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1) Before Breakfast and IMP Administration 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 
5) At a Feasible Time 
• Check on the use of concomitant diuretics 
• 12-Lead ECG (central) (once on Day 3 or Day 4) 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 
1.3.8 
Treatment Period (Day 5) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 

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1) Before Breakfast and IMP Administration 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 
5) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 
1.3.9 
Treatment Period (Day 6) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 
1) Before Breakfast and IMP Administration 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 

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• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 
5) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 
1.3.10 
Treatment Period (Day 7) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 
1) Before Breakfast and IMP Administration 
• Plasma drug concentration (at the time specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• Body weight 

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• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Urine volume in a time point set, fluid intake in a time point set, and fluid 
balance in a time point set (at the times specified in Table 1.3-2) 
• Urine osmolality in a time point set and urine electrolyte (sodium, potassium) 
concentrations in a time point set 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) After IMP Administration 
• Plasma drug concentration (at the time specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• Blood sampling and urine collection for storage of biomarker samples 
(optional) (at the time specified in Table 1.3-2) 
• Urine volume in a time point set, fluid intake in a time point set, and fluid 
balance in a time point set (at the times specified in Table 1.3-2) 
• Urine osmolality in a time point set and urine electrolyte (sodium, potassium) 
concentrations in a time point set 
 
5) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
• Chest X-ray (cardiothoracic ratio and pulmonary congestion) 
• NYHA Functional Classification 
• 12-Lead ECG (central) 
 
6) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 

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• Physical examination 
• Check on concomitant medications/therapies 
 
1.3.11 
Treatment Period (Day 8) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 
1) Before Breakfast and IMP Administration 
• Plasma drug concentration (at the time specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• Pharmacodynamic laboratory tests (serum cystatin C concentration, serum 
creatinine concentration, plasma AVP concentration, plasma renin activity, 
plasma aldosterone concentration, plasma BNP concentration, serum troponin 
I concentration, and serum NT-proBNP concentration) 
• CA125 
• Clinical laboratory tests 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 

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5) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 
1.3.12 
Treatment Period (Day 9 and Day 11) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 
1) Before Breakfast and IMP Administration 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 
5) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 

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1.3.13 
Treatment Period (Day 10) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 
1) Before Breakfast and IMP Administration 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 
5) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 

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1.3.14 
Treatment Period (Day 12) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 
1) Before Breakfast and IMP Administration 
• Plasma drug concentration (at the time specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 
5) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 

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1.3.15 
Treatment Period (Day 13) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 
1) Before Breakfast and IMP Administration 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 
5) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 
1.3.16 
Treatment Period (Day 14) 
The investigator or subinvestigator will perform the following examinations and 
investigations. 

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1) Before Breakfast and IMP Administration 
• Plasma drug concentration (at the time specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) concentrations and serum osmolality 
(at the time specified in Table 1.3-2) 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
Subjects will be instructed to urinate completely after breakfast and by the time 
immediately before administration, and measurement of urine volume and fluid 
intake will be started after complete urination immediately before administration, 
which will be set as the starting time point to evaluate the items shown below. 
Urine volume in a time point set, fluid intake in a time point set, and fluid balance 
in a time point set (at the times specified in Table 1.3-2) will also be evaluated. 
• Urine volume in a time point set, fluid intake in a time point set, and fluid 
balance in a time point set (at the times specified in Table 1.3-2) 
• Urine osmolality in a time point set, urine electrolyte (sodium, potassium) 
concentrations in a time point set, and urine aquaporin 2 concentration in a 
time point set 
 
3) IMP Administration 
The investigator or subinvestigator will confirm that the subject has taken the IMP 
completely, and record the date and time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
 
4) After IMP Administration 
• Plasma drug concentration (at the time specified in Table 1.3-2) 
• Urine volume in a time point set, fluid intake in a time point set, and fluid 
balance in a time point set (at the times specified in Table 1.3-2) 
• Urine osmolality in a time point set, urine electrolyte (sodium, potassium) 
concentrations in a time point set, and urine aquaporin 2 concentration in a 
time point set 
 
5) At a Feasible Time after IMP Administration 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
 

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6) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
 
1.3.17 
Treatment Period (End of Treatment Examination on Day 15 or 
Withdrawal Examination: the Day after the Final IMP 
Administration) 
The investigator or subinvestigator will perform the following examinations and 
investigations on the day after the final IMP administration or at discontinuation. 
Completion of the EOT examination or withdrawal examination will be entered in the 
IWRS. 
1) Before Breakfast 
• Plasma drug concentration (at the time specified in Table 1.3-2; only for 
completers and early completers) 
• Serum electrolyte (sodium, potassium) concentrations, and serum osmolality 
• Pharmacodynamic laboratory tests (serum cystatin C concentration, serum 
creatinine concentration, plasma AVP concentration, plasma renin activity, 
plasma aldosterone concentration, plasma BNP concentration, serum troponin 
I concentration, and serum NT-proBNP concentration) 
• CA125 
• Clinical laboratory tests 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) After Breakfast 
• Plasma drug concentration (at the time specified in Table 1.3-2; only for 
completers and early completers) 
Subjects will be instructed to urinate completely after breakfast, and 
measurement of urine volume and fluid intake will be started after complete 
urination, which will be set as the starting time point to evaluate the items 
shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance (only for early 
completers and withdrawals) 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations (only for early completers and withdrawals) 

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• Urine volume in a time point set, fluid intake in a time point set, and fluid 
balance in a time point set (at the times specified in Table 1.3-2; only for 
completers) 
• Urine osmolality in a time point set, and urine electrolyte (sodium, potassium) 
concentrations in a time point set (only for completers) 
 
3) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
• Chest X-ray (cardiothoracic ratio and pulmonary congestion) 
• NYHA Functional Classification 
• 12-Lead ECG (central) 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
• Plasma drug concentration (only for withdrawals) 
• Echocardiography (disc method [modified Simpson method]) (LVEDV, 
LVESV, and LVEF) (once on Day 15 or in the period from the day after the 
final IMP administration to 2 days after the final IMP administration) 
 
1.3.18 
Post-treatment Observation Period (Post-treatment Examination 
on Day 16: 2 Days after the Final IMP Administration) 
The investigator or subinvestigator will perform the following examinations and 
investigations 2 days after the final IMP administration. 
1) At a Specified Time 
• Plasma drug concentration (at the time specified in Table 1.3-2; only for 
completers and early completers) 
 
2) Before Breakfast 
• Serum electrolyte (sodium, potassium) concentrations, and serum osmolality 
• Clinical laboratory tests 
• Body weight 
• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 

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3) After Breakfast 
Subjects will be instructed to urinate completely after breakfast, and measurement 
of urine volume and fluid intake will be ended when the complete urination after 
breakfast is finished, which will be set as the ending time point to evaluate the 
items shown below. 
• Daily urine volume, daily fluid intake, and daily fluid balance (only for early 
completers and withdrawals) 
• Daily urine osmolality and daily urine electrolyte (sodium, potassium) 
concentrations (only for early completers and withdrawals) 
• Urine volume in a time point set, fluid intake in a time point set, and fluid 
balance in a time point set (at the times specified in Table 1.3-2; only for 
completers) 
• Urine osmolality in a time point set, and urine electrolyte (sodium, potassium) 
concentrations in a time point set (only for completers) 
 
4) At a Feasible Time 
• Check on the use of concomitant diuretics 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
• 12-Lead ECG (central) 
• Adverse events 
• Physical examination 
• Check on concomitant medications/therapies 
• Echocardiography (disc method [modified Simpson method]) (LVEDV, 
LVESV, and LVEF) (once on Day 15 or in the period from the day after the 
final IMP administration to 2 days after the final IMP administration) 
 
1.3.19 
Follow-up Examination (Day 24 to Day 28: 10 to 14 Days after the 
Final IMP Administration) 
The investigator or subinvestigator will perform the following examinations and 
investigations between 10 and 14 days after the final IMP administration. Subjects who 
have been discharged will undergo the examinations and investigations on an outpatient 
basis. Discharge information will be recorded in the eCRF. 
1) Before Breakfast 
• Serum electrolyte (sodium, potassium) concentrations, and serum osmolality 
• CA125 
• Clinical laboratory tests 
• Body weight 

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• Vital signs (systolic and diastolic blood pressures, pulse rate, and body 
temperature) 
 
2) At a Feasible Time 
• Plasma drug concentration (only for completers and early completers) 
• Congestive findings (lower limb edema, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound) 
• 12-Lead ECG (central) 
• Adverse events 
• Physical examination 
• Check on the use of concomitant medications/therapies 
• Urine pregnancy test (only for female subjects of childbearing potential; if the 
test result is positive, a serum pregnancy test will be performed.) 
 

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2 
Introduction 
OPC-131461 is a new orally available vasopressin antagonist with vasopressin V1a and 
V2 receptor dual antagonism. As OPC-131461 is expected to become a treatment for 
cardiac edema, etc, Otsuka Pharmaceutical Co., Ltd. (hereinafter, Otsuka) decided to 
begin the clinical development of OPC-131461. 
Refer to the current OPC-131461 Investigator’s Brochure (IB) for more detailed 
information. 
2.1 
Trial Rationale 
In patients with congestive heart failure (CHF), congestive edematous symptoms 
secondary to heart failure such as jugular venous distension, lower limb edema, and 
hepatomegaly are observed. Diuretics (mainly loop diuretics) are commonly used to 
reduce edematous symptoms, but Samsca® (tolvaptan) is recommended to be used for the 
improvement of volume overload when adequate response is not obtained despite having 
received the conventional diuretics.1,2 While widely used in clinical practice, tolvaptan is 
likely to induce adverse reactions due to its pharmacological action in the early stage of 
treatment. Particularly, hypernatremia-related adverse reactions (eg, hypernatremia and 
increased serum sodium concentrations) may lead to serious adverse reactions such as 
disturbed consciousness and osmotic demyelination syndrome. When using tolvaptan, 
healthcare professionals are required to take additional measures in order to ensure the 
safety of patients, including hospitalization of patients to begin or resume tolvaptan 
treatment and frequent monitoring of serum sodium concentrations particularly on the 
day that tolvaptan treatment is started or resumed. This is a challenge of tolvaptan 
compared to other conventional diuretics. 
OPC-131461 was studied in a phase 1, single and multiple dose clinical trial of 
OPC-131461 suspension in healthy adult male subjects (Protocol No. 351-102-00001; 
hereinafter referred to as “Japanese phase 1 single and multiple dose trial”), the results of 
which demonstrated that OPC-131461 suspension was safe and tolerable when orally 
administered at 5 to 320 mg as a single dose or at 5, 40, and 100 mg as multiple doses for 
14 days. OPC-131461 was also confirmed to be antagonistic to vasopressin V2 receptors 
as seen in tolvaptan and have a longer half-life than tolvaptan, with a slow increase in the 
plasma drug concentration to reach the steady state. These findings indicate that 
OPC-131461 can be considered to become a novel aquaretic in patients with CHF that 
can reduce pharmacology-related adverse reactions that likely occur early in treatment, 
which is a challenge of tolvaptan, by using the dose at which the aquaretic effect is 

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exerted more slowly at the early stage of treatment compared to tolvaptan and is expected 
to adequately reduce body weight and improve congestive findings by continued 
treatment even though the aquaretic effect at the early stage of treatment is slower than 
tolvaptan. On the other hand, there is no clinical experience with OPC-131461 in patients 
with CHF. Therefore, Otsuka has planned a Japanese phase 2 dose-ranging trial 
(hereinafter referred to as “the trial”) to investigate the dose response in respect of weight 
decrease following repeated oral administration of OPC-131461 at 1, 2, 5, and 10 mg or 
placebo in patients with CHF with volume overload despite having received diuretics 
other than vasopressin antagonists. 
In conclusion, the conduct of the trial can be justified from scientific and ethical 
standpoints. 
2.2 
Background 
OPC-131461 is a new orally available vasopressin V1a and V2 receptor dual antagonist 
developed by Otsuka. Samsca® (tolvaptan), a V2 receptor antagonist as is OPC-131461, 
was first granted marketing approval as an oral aquaretic agent in Japan in October 2010, 
and it has proved to be a useful treatment for heart failure patients with volume overload 
despite having received the conventional diuretics. Although tolvaptan is the only 
vasopressin receptor antagonist orally available for the treatment of volume overload 
secondary to heart failure, there are challenges in clinical practice that treatment of 
tolvaptan requires to be started or resumed under hospitalization since hypernatremia-
related adverse reactions may occur and lead to serious adverse reactions due to the 
potent aquaretic effect at the early stage of starting the treatment and that it particularly 
requires a frequent measurement of serum sodium concentration on the day of start or 
resumption of administration. A vasopressin receptor antagonist that resolves those 
challenges is called for by medical institutions. 
OPC-131461 is characterized mainly by having almost the same affinity as tolvaptan for 
human arginine vasopressin (AVP) V2 receptors and approximately 4 times greater 
affinity than tolvaptan for V1a receptors. In a Japanese phase 1 single and multiple dose 
trial in healthy adult male subjects (Protocol No. 351-102-00001), OPC-131461 
suspension showed a dose-dependent aquaretic effect after being orally administered at 5 
to 320 mg as a single dose or at 5, 40, and 100 mg as multiple doses for 14 days. 
OPC-131461 administered as a suspension demonstrated AVP-induced platelet 
aggregation in a dose-dependent manner. These results suggest that OPC-131461 has not 
only an aquaretic effect based on vasopressinV2 receptor antagonism, similarly to 
tolvaptan, but also vasopressinV1a receptor antagonism. In patients with heart failure, 

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vasopressinV1a receptor antagonism is expected to inhibit peripheral vasoconstriction, 
thereby suppressing an increase in cardiac afterload.3 
In a Japanese phase 1 single and multiple dose trial (Protocol No. 351-102-00001), the 
median time to maximum plasma concentration (tmax) was 2.00 to 4.00 hours and the 
mean terminal-phase elimination half-life (t1/2,z) was 20.9 to 29.8 hours after a single oral 
administration of OPC-131461 suspension at 5 to 320 mg, whereas in a Japanese phase 1 
trial of tolvaptan (Protocol No. 156-00-001), the median tmax was 2.00 to 3.00 hours and 
the mean t1/2,z was 2.92 to 9.33 hours after a single administration of tolvaptan at 15 to 
120 mg, confirming that OPC-131461 has a similar tmax to tolvaptan and a longer t1/2,z 
than tolvaptan. These findings suggest that plasma OPC-131461 concentrations slowly 
increase to the steady state, thus indicating that OPC-131461 may reduce occurrences of 
pharmacology-related adverse reactions such as hypernatremia, an event that occurs early 
in the treatment with tolvaptan, by using the dose at which an aquaretic effect is exerted 
more slowly than tolvaptan and that OPC-131461 is also expected to exert the same level 
of pharmacological effect as that of tolvaptan by continued treatment. The safety and 
tolerability of OPC-131461 suspension was confirmed when orally administered as a 
single dose at 5 to 320 mg and as multiple doses at 5, 40, and 100 mg for 14 days. 
A phase 1 trial to investigate the relative bioavailability (BA) of OPC-131461 suspension 
and OPC-131461 tablet and the effect of food on the pharmacokinetics (PK) of 
OPC-131461 (Protocol No. 351-102-00002; hereinafter referred to as “Japanese phase 1 
relative BA and food effect trial”) demonstrated that OPC-131461 tablet had good 
relative BA compared to OPC-131461 suspension and was not markedly affected by 
food. 
OPC-131461 may be a solution to the challenges of tolvaptan when used at the dose at 
which the aquaretic effect is exerted more slowly than tolvaptan in the early stage of 
treatment to prevent a rapid increase in serum sodium concentrations and thus improve 
volume overload in a safer manner in patients with CHF. 
Based on the above, Otsuka has planned the trial to evaluate the efficacy and safety of 
OPC-131461 tablet in patients with CHF. 
2.2.1 
Nonclinical Data 
In a radiolabeled ligand ([3H]-AVP) binding studies using HeLa cells expressing human 
AVP receptors and rat tissue membrane preparations, OPC-131461 inhibited [3H]-AVP 
binding to human AVP V2 and V1a receptors with inhibition constants (Ki) of 0.70 ± 0.06 

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and 3.99 ± 0.94 nM, respectively. In this study, the Ki values of tolvaptan for human 
AVP V2 and V1a receptors were 0.61 ± 0.03 and 14.2 ± 5.3 nM, respectively. These 
results showed that OPC-131461 and tolvaptan had almost the same level of binding 
affinity for human AVP V2 receptors and that the binding affinity of OPC-131461 for 
human AVP V1a receptors was higher than that of tolvaptan. OPC-131461 showed no 
binding affinity for human AVP V1b receptors. In studies of effects on 
AVP (80 nM)-induced human platelet aggregation and AVP (1 nM)-induced cyclic 
adenosine 3',5'-monophosphate (cAMP) production in V2 receptor-expressing HeLa cells, 
OPC-131461 inhibited both platelet aggregation (50% inhibitory concentration [IC50] of 
157 ± 53 nM) and cAMP production (IC50 of 1.10 ± 0.14 nM) in a concentration-
dependent manner. Furthermore, OPC-131461 had no agonistic activity for human AVP 
V1a and V2 receptors. 
After oral administration to conscious Sprague-Dawley (SD) rats, OPC-131461 dose-
dependently increased the urine flow rate at 0.1 to 3 mg/kg and dose-dependently 
decreased urine osmolality at 0.1 to 3 mg/kg. At 0.3 mg/kg and higher, urine osmolality 
was lower than plasma osmolality (approximately 300 mOsm/kg H2O), suggesting that 
free water clearance was positive. Tolvaptan at 10 mg/kg also increased the urine flow 
rate and decreased urine osmolality. These results indicate that OPC-131461 has an 
aquaretic effect similar to that of tolvaptan. 
For the AVP-induced pressor response occurred in conscious male SD rats, oral 
administration of OPC-131461 at doses of 0.3 to 3 mg/kg significantly inhibited the 
AVP-induced pressor response in a dose-dependent manner. The inhibitory effect of 
OPC-131461 at 3 mg/kg lasted for 8 hours postdose with a high inhibition rate 
(approximately 70%), suggesting that OPC-131461 is an orally active and long-acting 
AVP V1a receptor antagonist. 
These results indicate that OPC-131461 is an orally active AVP V1a and V2 receptor 
antagonist. 
The protein binding of OPC-131461 was 99.5% to 99.7% in human serum. In vitro 
metabolism studies showed that cytochrome P450 (CYP) (CYP3A4) was involved in the 
metabolism of OPC-131461. 
OPC-131461 inhibited CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (for 
CYP3A4, two substrates, testosterone and midazolam, were used in the evaluation) and 
the Ki value was 3.74, 8.44, 12.6, 5.59, 8.37, and 3.07 μmol/L, respectively. OPC-131461 

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was found to induce the expression of CYP1A2, CYP2B6, and CYP3A4. OPC-131461 
was a substrate of human P-glycoprotein (P-gp) but not a substrate of breast cancer 
resistance protein (BCRP). OPC-131461 inhibited human P-gp and BCRP with an IC50 
value of 7.81 and 9.65 μmol/L, respectively. 
Safety pharmacology studies were conducted in rats and conscious dogs. OPC-131461 at 
a single dose of up to 1000 mg/kg had no effects on the central nervous system in rats. 
No effects on respiratory and cardiovascular function parameters were observed in 
conscious dogs at a single dose of up to 900 mg/kg. OPC-131461 had no effect on 
electrocardiogram (ECG) parameters in conscious dogs at a single oral dose of up to 
900 mg/kg but prolonged QT interval and corrected QT interval (QTc) after repeated oral 
administration at 300 and 900 mg/kg/day. 
In a repeated oral dose toxicity study, one female rat at 100 mg/kg/day was euthanized in 
a moribund state on Day 3 with notable body weight loss due to dehydration. Changes in 
hematological parameters, including decreased hemoglobin, and blood coagulation 
parameters were observed in rats at 1000 mg/kg/day. One male dog at 900 mg/kg/day in a 
4-week study and one male dog at 300 mg/kg/day in a 13-week study showed increased 
liver-related parameters and histopathological liver injury. 
Genotoxicity studies revealed that OPC-131461 was not mutagenic and did not cause 
chromosomal damage. 
In an embryo-fetal development study in rats, visceral and skeletal anomalies and 
variations were observed at 3 mg/kg/day or higher, although these incidences were low. 
At 100 mg/kg/day, an external anomaly and a slight increase in visceral variations were 
also observed. In rabbits, OPC-131461 had no effect on embryo-fetal development at up 
to 100 mg/kg/day, the highest dose tested. 
Please refer to the current version of the OPC-131461 IB for more detailed information 
on the results of nonclinical studies. 
2.2.2 
Clinical Data 
1) Phase 1 Single and Multiple Oral Dose Trial of OPC-13146 Suspension in 
Healthy Adult Male Subjects (Protocol No. 351-102-00001, Japan) 
This trial consisted of Part A in which OPC-131461 suspension at 5, 10, 20, 40, 
80, 160, and 320 mg was orally administered as a single dose and Part B in which 
OPC-131461 suspension at 5, 40, and 100 mg was orally administered as multiple 
doses for 14 days to evaluate the safety, tolerability, PK, and pharmacodynamics 
(PD) of oral OPC-131461 suspension in healthy adult male subjects. 
 

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a) Part A (Single Oral Administration) 
Of 56 healthy adult male subjects enrolled, 42 subjects (6 subjects/group) 
received a single oral administration of OPC-131461 suspension at 5, 10, 20, 
40, 80, 160, and 320 mg, and 14 control subjects (2 subjects/group) received a 
single oral administration of placebo. 
The maximum (peak) plasma concentration of the drug (Cmax), area under the 
concentration-time curve from time zero to infinity (AUC∞), and area under 
the concentration-time curve calculated to the last observable concentration at 
time t (AUCt) of OPC-131461 increased dose-dependently in subjects treated 
with a single oral dose of OPC-131461 suspension at 5 to 320 mg. The 
median tmax was 2.00 to 4.00 hours and the mean t1/2,z was 20.9 to 29.8 hours. 
The daily urine volume increased dose-dependently from baseline in all 
treatment groups, and OPC-131461 at 5 mg was associated with a daily urine 
volume equivalent to that after administration of tolvaptan at 15 mg (Protocol 
No. 156-00-001). Following OPC-131461 administration, the percent of 
inhibition of AVP-induced platelet aggregation increased from predose in 
each active group or placebo, with a marked increase at 20 mg or higher. 
Seventy-five adverse events (AEs) occurred in 33 of 42 OPC-131461-treated 
subjects (78.6%) and 3 AEs in 2 of 14 placebo-treated subjects (14.3%). The 
majority of AEs, except for 6 events in OPC-131461-treated subjects and 1 
event in placebo-treated subjects, were judged to be related to OPC-131461. 
All events were mild or moderate in severity, with no severe events reported. 
The AEs with a higher incidence were polyuria (29/42 subjects) and thirst 
(23/42 subjects). Among AEs considered to be related to the pharmacology of 
the investigational medicinal product (IMP), 9 events of orthostatic 
hypotension or blood pressure orthostatic decreased were reported in 8 of 42 
OPC-131461-treated subjects and 2 such events were reported in 2 of 14 
placebo-treated subjects. All of these events were mild in severity and 
resolved within 24 hours of onset. All the events were judged to be related to 
OPC-131461 with the exception of 1 event that occurred in 1 subject the day 
after single administration of OPC-131461 at 5 mg. Two AEs leading to trial 
discontinuation (hypernatraemia and orthostatic hypotension) were reported in 
2 subjects following single oral administration at the highest dose of 320 mg. 
Both events were judged to be related to OPC-131461, however, they were 
mild in severity and resolved within 24 hours of onset. Adverse reactions 
reported in more than 1 subject in any treatment group after single oral 
administration of OPC-131461 suspension at 5 to 320 mg are summarized in 
Table 2.2.2-1. 
 

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Table 2.2.2-1 
Adverse Reactions Reported in more than 1 Subject in Any 
Treatment Group after Single Oral Administration of 
OPC-131461 Suspension at 5 to 320 mg 
Preferred Term 
OPC-131461 
Placebo 
5 mg 
(N = 6) 
n (%) 
10 mg 
(N = 6) 
n (%) 
20 mg 
(N = 6) 
n (%) 
40 mg 
(N = 6) 
n (%) 
80 mg 
(N = 6) 
n (%) 
160 mg 
(N = 6) 
n (%) 
320 mg 
(N = 6) 
n (%) 
Total 
(N = 42) 
n (%) 
 
(N = 14) 
n (%) 
Thirst 
0 (0.0) 
1 (16.7) 
1 (16.7) 
4 (66.7) 6 (100.0) 5 (83.3) 6 (100.0) 23 (54.8) 
0 (0.0) 
Polyuria 
0 (0.0) 
1 (16.7) 
4 (66.7) 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 29 (69.0) 
0 (0.0) 
Orthostatic 
hypotension 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (16.7) 
0 (0.0) 
1 (16.7) 
2 (33.3) 
4 (9.5) 
2 (14.3) 
 
b) Part B (Repeated Oral Administration) 
Of 26 healthy adult male subjects enrolled, 5, 6, and 6 subjects received 
14-day repeated oral administration of OPC-131461 suspension at 
respectively 5, 40, and 100 mg and 9 control subjects (3 subjects/group) 
received 14-day repeated oral administration of placebo. 
The Cmax and area under the concentration-time curve from time zero to 
24 hours (AUC24h) of OPC-131461 increased dose-dependently in subjects 
treated with multiple oral doses of OPC-131461 suspension at 5, 40, and 
100 mg. The accumulation ratio for Cmax and AUC24h on Day 14 versus Day 1 
at 5, 40, and 100 mg was respectively 1.64, 0.915, and 0.731, and respectively 
1.60, 0.796, and 0.625. Fourteen days of oral administration of OPC-131461 
at 5 mg resulted in approximately 1.6-fold accumulation of Cmax and AUC24h, 
whereas at 40 and 100 mg, accumulation of Cmax and AUC24h decreased dose-
dependently. The median tmax was 1.50 to 3.00 hours and the mean t1/2,z was 
18.5 to 28.4 hours. The daily urine volume increased dose-dependently from 
baseline in all treatment groups and almost returned to the baseline urine 
volume 2 days after the final IMP administration. Following OPC-131461 
administration, the percent of inhibition of AVP-induced platelet aggregation 
increased from predose in each active group or placebo. 
Sixty-two AEs occurred in 15 of 17 OPC-131461-treated subjects (88.2%) 
and 4 AEs in 3 of 9 placebo-treated subjects (33.3%). The majority of AEs, 
except for 8 events in 6 OPC-131461-treated subjects and 1 event in one 
placebo-treated subject, were judged to be related to OPC-131461. All events 
were mild or moderate in severity, with no severe events reported. The AEs 
with a higher incidence were polyuria (13/17 subjects) and thirst (11/17 
subjects). Among AEs considered to be related to the pharmacology of the 
IMP, 22 events of orthostatic hypotension or blood pressure orthostatic 
decreased were reported in 7 of 17 OPC-131461-treated subjects and 3 such 
events were reported in 3 of 9 placebo-treated subjects. All of these events 
were mild in severity and judged to be related to OPC-131461. Two events in 
the 100 mg group took 3 days to resolve and all the other events resolved 
within approximately 24 hours of onset. In the 40 mg group, 2 AEs leading to 
treatment discontinuation (hypernatraemia and tonsillitis) were reported in 

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2 subjects. The event of hypernatraemia was judged to be related to 
OPC-131461 and was mild in severity and resolved within 24 hours after 
treatment discontinuation. The event of tonsillitis was judged to be unrelated 
to OPC-131461 and was moderate in severity and resolved 6 days after onset. 
Adverse reactions reported in more than 1 subject in any treatment group after 
repeated oral administration of OPC-131461 suspension at 5, 40, and 100 mg 
are summarized in Table 2.2.2-2. 
 
Table 2.2.2-2 
Adverse Reactions Reported in more than 1 Subject in Any 
Treatment Group after Repeated Oral Administration of 
OPC-131461 Suspension at 5, 40, and 100 mg 
Preferred Term 
OPC-131461 
Placebo 
5 mg 
(N = 5) 
n (%) 
40 mg 
(N = 6) 
n (%) 
100 mg 
(N = 6) 
n (%) 
Total 
(N = 17) 
n (%) 
 
(N = 9) 
n (%) 
Thirst 
1 (20.0) 
6 (100.0) 
4 (66.7) 
11 (64.7) 
0 (0.0) 
Blood pressure 
orthostatic 
decreased 
2 (40.0) 
0 (0.0) 
2 (33.3) 
4 (23.5) 
1 (11.1) 
Headache 
0 (0.0) 
2 (33.3) 
0 (0.0) 
2 (11.8) 
0 (0.0) 
Polyuria 
1 (20.0) 
6 (100.0) 
6 (100.0) 
13 (76.5) 
0 (0.0) 
Orthostatic 
hypotension 
1 (20.0) 
1 (16.7) 
2 (33.3) 
4 (23.5) 
2 (22.2) 
 
No serious adverse events (SAEs) including death were reported in any treatment 
group in Parts A and B. In addition, there were no clinically significant findings 
or abnormalities in prothrombin time-international normalized ratio (PT-INR) or 
activated partial thromboplastin time (APTT) for assessment of bleeding/bleeding 
tendency or in 12-lead ECG. 
In conclusion, OPC-131461 suspension was safe and tolerable when administered 
as a single oral dose of 5 to 320 mg or as multiple oral doses of 5, 40, and 100 mg 
for 14 days. 
 
2) Phase 1 Relative Bioavailability and Food Effect Trial of OPC-131461 in Healthy 
Adult Male Subjects (Protocol No. 351-102-00002, Japan) 
In this 2-group, 2-period crossover trial, healthy adult male subjects received 
single oral administration of OPC-131461 suspension at 20 mg or four 
OPC-131461 5-mg tablets in the relative BA part and the food effect part. 
Preliminary PK and safety results were available when the original version of this 
protocol was finalized. 
No SAEs including death were reported in any treatment group. 
 

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a) Relative BA part 
A total of 8 healthy adult male subjects (4 in the suspension-first group and 4 
in the tablet-first group) orally received OPC-131461 suspension or 
OPC-131461 tablets to investigate the PK of both formulations. 
The geometric mean ratio for Cmax and area under the concentration-time 
curve (AUC) after OPC-131461 tablet (5 mg) administration at 20 mg versus 
OPC-131461 suspension administration at 20 mg was respectively 0.89 and 
1.01. The median tmax after OPC-131461 suspension administration at 20 mg 
and after OPC-131461 tablet (5 mg) administration at 20 mg was respectively 
2.50 and 3.50 hours and the mean t1/2,z was respectively 24.0 and 23.7 hours. 
The AEs with a higher incidence were polyuria and thirst. All these events 
were mild in severity, judged to be related to OPC-131461, and resolved. 
Apart from polyuria and thirst, no other AEs probably related to the 
pharmacology of the IMP were reported. 
 
b) Food effect part 
A total of 8 healthy adult male subjects (4 in the tablet fasting-state-first group 
and 4 in the tablet fed-state-first group) orally received OPC-131461 5-mg 
tablets to investigate the effect of food (high-fat meal) on the PK of 
OPC-131461. 
The Cmax and AUC after administration of OPC-131461 5-mg tablets at 
20 mg in the fed state were respectively 1.20 and 1.14 times those after 
administration in the fasting state. The median tmax was 3.50 hours and the 
mean t1/2,z was 24.7 hours regardless of whether OPC-131461 5-mg tablets at 
20 mg were administered in the fed state or in the fasting state. 
The AEs with a higher incidence were polyuria and thirst. All these events 
were mild in severity, judged to be related to OPC-131461, and resolved. 
Apart from polyuria and thirst, no other AEs probably related to the 
pharmacology of the IMP were reported. 
Please refer to the current version of the OPC-131461 IB for more detailed 
information on the results of clinical trials. 
 
2.3 
Known and Potential Risks and Benefits 
Although there is no clinical experience of OPC-131461 in patients with CHF, a Japanese 
phase 1 single and multiple dose trial in healthy adult male subjects has demonstrated that 
OPC-131461 possesses vasopressin V2 receptor antagonism as observed with tolvaptan, 
indicating that OPC-131461 may offer similar benefits to those of tolvaptan. Tolvaptan is 
effective in reducing body weight and improving cardiac edema-related findings (jugular 
venous distension, hepatomegaly, and lower limb edema) in patients with CHF. 

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Potential risks of treatment with OPC-131461 in patients with CHF were indicated by 
several results from safety pharmacology and toxicity studies in rats and dogs (see the 
current version of IB for detailed information) as well as changes that may occur in 
association with the pharmacology of OPC-131461, including hypotension, bleeding, 
increased serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia. 
Events associated with the pharmacological action of OPC-131461 were observed in a 
Japanese phase 1 single and multiple dose trial of OPC-131461 suspension in healthy 
adult male subjects and a Japanese phase 1 relative bioavailability and food effect trial of 
OPC-131461 tablet, which were conducted to date. Additional information on these trials 
is provided in Section 2.2.2. The adverse reactions reported in these trials may also occur 
in patients with CHF and it is recommended to closely monitor the subjects of the present 
trial and allow them to drink water without restriction. 
It has been confirmed that OPC-131461 tablet has similar oral absorbability to that of 
OPC-131461 suspension and is associated with only a minor food effect. Given these 
findings, the potential risks of OPC-131461 tablet are comparable to those of 
OPC-131461 suspension. 
Trial sites will receive updated versions of the IB, when available, and trial sites should 
refer to the most current version as needed. 
 

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3 
Objectives and Endpoints 
The objectives and endpoints of this trial are shown in Table 3-1. 
 
Table 3-1 
Trial Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives: 
To investigate the dose response in respect of 
weight decrease following repeated oral 
administration of OPC-131461 at 1, 2, 5, and 
10 mg or placebo in patients with CHF with 
volume overload despite having received diuretics 
other than vasopressin antagonists 
Primary Efficacy Endpoint: 
Change in body weight from baseline to last 
assessment time point (the day after investigational 
medicinal product [IMP] administration) by Day 8 
 
Secondary Efficacy Endpoints: 
Change in body weight from baseline to last 
assessment time point (the day after IMP 
administration) by Day 15 
 
Percent change in body weight from baseline to 
last assessment time point (the day after IMP 
administration) by Day 8 
 
Percent change in body weight from baseline to 
last assessment time point (the day after IMP 
administration) by Day 15 
 
Improvement of or change in congestive findings 
(lower limb edema, pulmonary congestion, jugular 
venous distension, hepatomegaly, cardiothoracic 
ratio, pulmonary rales, and cardiac third sound) 
from baseline to last assessment time point (the 
day of IMP administration) by Day 7 
 
Improvement of or change in congestive findings 
(lower limb edema, pulmonary congestion, jugular 
venous distension, hepatomegaly, cardiothoracic 
ratio, pulmonary rales, and cardiac third sound) 
from baseline to last assessment time point (the 
day after IMP administration) by Day 15 
 
Congestive findings (lower limb edema, 
pulmonary congestion, jugular venous distension, 
hepatomegaly, cardiothoracic ratio, pulmonary 
rales, and cardiac third sound), time to resolution 
of congestive findings, and the New York Heart 
Association (NYHA) Functional Classification 
Secondary Objectives: 
To confirm the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics of 
OPC-131461 versus placebo in patients with CHF 
with volume overload despite having received 
diuretics other than vasopressin antagonists 
Safety: 
Adverse events (AEs), clinical laboratory test 
values, physical examination findings, vital signs, 
and 12-lead electrocardiogram (ECG) 
 
Pharmacodynamic endpoint: 
Serum osmolality, serum electrolyte (sodium, 
potassium) concentrations, serum troponin I 

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Table 3-1 
Trial Objectives and Endpoints 
Objectives 
Endpoints 
concentration, serum N-terminal pro-brain 
natriuretic peptide (NT-proBNP) concentration, 
serum creatinine concentration, serum cystatin C 
concentration, estimated glomerular filtration rate 
(estimated glomerular filtration rate using the 
creatinine [eGFRcre], estimated glomerular 
filtration rate using the cystatin C [eGFRcys]), 
plasma arginine vasopressin (AVP) concentration, 
plasma brain natriuretic peptide (BNP) 
concentration, plasma renin activity, and plasma 
aldosterone concentration 
 
Daily urine volume/fluid intake/fluid balance 
Urine volume/fluid intake/fluid balance in a time 
point set 
Urine volume/fluid intake/fluid balance per hour 
Urine osmolality, urine sodium excretion, urine 
potassium excretion, urine aquaporin 2 
concentration, and free water clearance 
 
Pharmacokinetic endpoint: 
Plasma concentrations and PK parameters of 
OPC-131461 and its metabolites 
Exploratory Objective: 
To conduct an exploratory investigation of OPC-
131461 compared to placebo. 
Exploratory endpoint: 
Carbohydrate antigen 125 (CA125), 
echocardiography for left ventricular ejection 
fraction (LVEF) 
 
Section 9.4 describes the statistical analysis of the endpoints. 
 
4 
Trial Design 
4.1 
Type/Design of Trial 
In this multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-
ranging trial, 155 patients with CHF with volume overload, despite having received 
diuretics other than vasopressin antagonists, will be randomized to receive OPC-131461 
1 mg, 2 mg, 5 mg, or 10 mg, or placebo (31 subjects/group) to investigate the dose 
response of OPC-131461 in respect of change in body weight from baseline at 
completion of 14 days of repeated oral administration. The trial design schematics is 
shown in Figure 1.2-1. 
The trial comprises the screening period, run-in period, treatment period, post-treatment 
observation period, and follow-up period. Subjects must be hospitalized from the day 

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before the run-in period through the end of post-treatment examination. Once the post-
treatment examination is finished, outpatient visits will be permitted. 
After obtaining written informed consent from patients, the investigator or 
subinvestigator will perform the screening examination, determine eligibility of patients, 
and enroll eligible patients in the trial. Day 1 is defined as the day when the first dose of 
IMP is administered. The dose and regimen of any concomitant diuretics must remain 
unchanged from Day −3 in the run-in period through the end of the post-treatment 
examination. The use of diuretics, changes in body weight, and presence or absence of 
congestive findings during the run-in period will be assessed, and only subjects who meet 
the inclusion criteria for proceeding to the treatment period will be randomized to one of 
the treatment groups and then proceed to the treatment period. 
The investigator or subinvestigator will allocate the IMP to subjects in a double-blinded 
fashion using the interactive web response system (IWRS) and then administer the IMP 
to them. Each subject will receive one of the following combinations in accordance with 
his or her assigned treatment group: only OPC-131461 tablets (1-mg or 5-mg tablets), 
OPC-131461 tablet (1-mg or 5-mg tablets) plus placebo tablet, or only placebo tablets. 
During the treatment period, subjects will orally receive the IMP once daily for 14 days.  
However, the treatment will be terminated before completing 14 days of treatment, if the 
investigator or subinvestigator judges that no further improvement of volume overload is 
necessary in a case that all congestive findings present at baseline are resolved or in other 
cases. Subjects who complete the trial or who discontinue the trial after receiving the 
IMP will undergo the end-of-treatment (EOT) examination on the day after the final IMP 
administration, post-treatment examination 2 days after the final IMP administration, and 
follow-up examination 10 to 14 days after the final IMP administration. Subjects will also 
be followed up for AEs, as necessary. 
All subjects should undergo EOT/withdrawal examination, post-treatment observation, 
and follow-up after the final IMP administration even if the actual treatment duration is 
less than 14 days as specified in the protocol. 
The trial duration for each subject is from informed consent to the end of the follow-up 
examination. 
4.2 
Scientific Rationale for Trial Design 
The subjects of this trial are patients with CHF who have volume overload despite 
treatment with diuretics other than vasopressin receptor antagonists. This is the same 
condition as that of the target patients for whom tolvaptan has been approved for 

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marketing. To compare the efficacy, safety, and pharmacological characteristics of 
OPC-131461 to those of tolvaptan 15 mg for characterization, the designs of a phase 3 
confirmatory trial (protocol No. 156-06-002) and clinical pharmacology trial (protocol 
No. 156-06-004) of tolvaptan were used as references. For this trial, it is appropriate to 
use placebo as a comparator to investigate the dose-response relationship of OPC-131461 
in patients with CHF. Subjects are to be hospitalized to ensure safety and the appropriate 
evaluation of OPC-131461. 
To investigate the dose response of OPC-131461 with respect to weight decrease and 
improvement of congestive findings, a 15-day treatment period is required, including a 
14-day dosing period and the protocol-specified EOT examination on the day after the 
final IMP administration. For the rationale for the dosing period, see Section 4.3. 
As a period required for the evaluation of OPC-131461, the post-treatment observation 
period is scheduled for 2 days after the final IMP administration. Because prolonged 
hospitalization is considered to be clinically unfavorable, subjects may be discharged 
when the post-treatment examination indicates no safety concerns. As for the follow-up 
period, the follow-up examination is scheduled on a day between 10 and 14 days after the 
final IMP administration in the trial. Based on the results of a Japanese phase 1 single and 
multiple oral dose trial of OPC-131461 (protocol No. 351-102-00001), t1/2,z after the final 
administration of multiple oral doses of OPC-131461 suspension (5, 40, or 100 mg), once 
daily for 14 days in healthy adult males was 18.5 to 28.4 hours on average, and t1/2,z with 
a single dose (5 to 320 mg) was almost within this range, as well. Subjects of this trial (ie, 
patients with CHF) may experience decreased blood flow in each organ as well as 
decreased hepatic metabolism due to decreased hepatic blood flow compared to healthy 
adults, and therefore, different PK from that in healthy adults may be seen.4 For this 
reason, a simulation was performed to predict PK in patients with CHF based on the 
population PK model using the trial results. As a result, it was suggested that the median 
t1/2,z after the final administration of multiple oral doses of OPC-131461 suspension once 
daily for 14 days was 50.1 hours in patients with CHF. These results suggest that 
OPC-131461 would be eliminated from the body 10 or more days after the final 
administration equivalent to 5 times the elimination half-life or more. At the same time, 
the pharmacological action of OPC-131461 would have also been lost, and adverse 
reactions related to the pharmacological action would have been resolved. Therefore, a 
follow-up examination on a day between 10 and 14 days after the final IMP 
administration is adequate as a safety observation period. 
Based on the above, the trial design has been judged to be scientifically and ethically 
justifiable. 

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4.3 
Dosing Rationale 
• Dosage regimen: Oral administration once daily 
• Dose: OPC-131461 at 1 mg/day, 2 mg/day, 5 mg/day, 10 mg/day, or 0 mg 
• Treatment duration: 14 days (However, the treatment will be terminated before 
completing 14 days of treatment, if the investigator or subinvestigator judges that no 
further improvement of volume overload is necessary in a case that any of congestive 
findings [lower limb edema, pulmonary congestion, jugular venous distension, 
hepatomegaly, pulmonary rales, and cardiac third sound] were resolved or in other 
cases.) 
 
Rationale 
Regarding the dosage regimen and dose, a simulation on urine volume in 24 hours was 
performed to predict PK/PD in patients with CHF. The results of this simulation 
suggested that multiple doses of OPC-131461 suspension 2 to 10 mg, once daily for 
7 days could achieve the urine volume observed during treatment with tolvaptan 7.5 to 
15 mg, and that even OPC-131461 suspension 1 mg might exert a diuretic action. The 
simulation described above also predicted that the median Cmax and AUC24h after 
multiple doses of OPC-131461 suspension 1 to 10 mg for 14 days would be up to 
196 ng/mL and 3860 ng∙h/mL, respectively, suggesting that they would not exceed the 
exposure with confirmed safety and tolerability after multiple oral doses of OPC-131461 
suspension 5, 40, or 100 mg for 14 days in the Japanese phase 1 single and multiple oral 
dose trial of OPC-131461 suspension in healthy adults (protocol No. 351-102-00001) 
(mean Cmax and AUC24h after multiple oral doses of OPC-131461 suspension 100 mg for 
14 days: 520 ng/mL and 4440 ng∙h/mL, respectively). The results of the Japanese phase 1 
trial to investigate the relative BA of OPC-131461 suspension and OPC-131461 tablet 
(5-mg tablet), as well as the effect of food on the PK of OPC-131461 tablet (5-mg tablet) 
(protocol No. 351-102-00002) showed no substantial difference in BA between 
OPC-131461 suspension 20 mg and OPC-131461 tablet (5-mg tablet) 20 mg in healthy 
adult males. In addition, the dissolution test suggested that the dissolution rate for 
OPC-131461 tablet (1-mg tablet) was higher than that of OPC-131461 tablet (5-mg 
tablet) and lower than that of OPC-131461 suspension. These results suggested that no 
marked difference in BA among OPC-131461 tablet (1-mg tablet), OPC-131461 tablet 
(5-mg tablet), and OPC-131461 suspension. As for the effect of food on the PK of 
OPC-131461 tablet (5-mg tablet) 20 mg, the Cmax and AUC were 1.20 times and 
1.14 times greater than those after administration under fasting conditions, respectively, 
indicating that food has little effect on the efficacy evaluation or safety. Based on the 
above, the dosage and administration were set as follows: this drug was orally 

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administered once daily at 1 to 10 mg; and 1, 2, 5, and 10 mg were set as 4 dose levels, so 
that the common ratio is between 2 and 2.5, inclusive. 
Regarding treatment duration, a Japanese phase 3 trial2 demonstrated that tolvaptan, 
which has a vasopressin receptor antagonism similar to OPC-131461, significantly 
improved volume overload in patients with CHF compared to placebo when administered 
at 15 mg for 7 days. To characterize OPC-131461 by comparing the results of this trial to 
those of the above-mentioned Japanese phase 3 trial of tolvaptan, the primary endpoint in 
this trial is set as the change in body weight from baseline to the last assessment time 
point (the day after IMP administration) by Day 8. Daily urine volume on and after the 
second day of multiple doses of tolvaptan was much lower than that on the first day, 
whereas the results of the above-mentioned simulation showed that daily urine volume 
was maintained or increased on and after the second day of multiple doses of 
OPC-131461 suspension, which indicates that the diuretic action of OPC-131461 lasts 
throughout the treatment period. Even if the aquaretic action of OPC-131461 in the early 
stage after the start of treatment is exerted more slowly than that of tolvaptan, an 
adequate weight decrease and improvement of congestive findings can be expected as 
long as treatment is continued. However, in treatment at a dose level where the aquaretic 
action in the early stage after the start of treatment is assumed to be exerted slowly, it 
may take longer than the duration of tolvaptan treatment (7 days) to reduce the body 
weight and improve congestive findings. Therefore, this trial adopts a 14-day treatment, 
which was confirmed to be tolerable in the Japanese phase 1 single and multiple oral dose 
trial. The treatment is to be terminated before completing the 14-day treatment if the 
investigator or subinvestigator judges that no further improvement of volume overload is 
necessary in a case that all congestive findings present at baseline are resolved or in other 
cases. 
4.4 
End of Trial Definition 
The end-of-trial date is defined as the last date of trial contact, or the date of final contact 
attempt as recorded on the post-treatment follow-up electronic case report form (eCRF) 
page for the last subject completing or withdrawing from the trial. 
4.5 
Definition of Completed Subjects 
The treatment period is defined as the period during which subjects are evaluated for the 
primary and/or secondary objectives of the trial, irrespective of whether or not the 
subjects actually take all doses of the IMP. Subjects who complete the 14-day treatment 
and the evaluation at the last scheduled visit during the treatment period are defined as 
trial completers. Subjects who terminate treatment before completing 14 days of 

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treatment, because the investigator or subinvestigator judges that no further improvement 
of volume overload is necessary in a case that all congestive findings (lower limb edema, 
pulmonary congestion, jugular venous distension, hepatomegaly, pulmonary rales, or 
cardiac third sound) present at baseline are resolved or in other cases, and who undergo 
the evaluation at the last scheduled visit during the treatment period are defined as early 
completers. For the purposes of this trial, early completers will also be considered as trial 
completers. Subjects who fall under the conditions in Section 7.3.2 are defined as 
withdrawals. All subjects will undergo the EOT/withdrawal examination, post-treatment 
examination, and follow-up examination. 
 
5 
Trial Population 
A total of 155 Japanese male and female subjects (31 subjects each in 5 groups; the target 
number of subjects who will begin the trial treatment) who are between the ages of 18 
and 89 years, inclusive at the time of informed consent, and who are suffering from CHF 
with volume overload (lower limb edema, pulmonary congestion, or jugular venous 
distension) despite having received diuretics other than vasopressin receptor antagonists 
will be enrolled in the trial. 
5.1 
Subject Selection and Numbering 
Subjects will be assigned a unique subject identifier (ID; site number [3 digits] + subject 
number [‘S’ + 5 digits]) upon providing written consent. The site numbers will be 
designated by the sponsor. The subject numbers will be assigned serially from S00001 in 
the order of informed consent at each site. Each site will prepare and retain a list of all 
subjects who have given consent and their subject ID numbers. 
5.2 
Eligibility Criteria 
Eligibility criteria exceptions, by either the investigator or the subinvestigator, will not be 
permitted in this trial. 
5.2.1 
Inclusion Criteria 
Subjects are required to meet the following inclusion criteria when assessed: 
5.2.1.1 
Screening Period 
Subjects who meet all of the following inclusion criteria (screening period) will be 
selected. 

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1) 
Subjects with CHF with any of lower limb edema, pulmonary congestion, or jugular venous 
distension due to volume overload. Subjects with pulmonary congestion confirmed by a chest X-ray 
taken within 14 days before informed consent may be included. 
2) 
Subjects undergoing any of the following diuretic therapies (including subjects scheduled to begin 
such therapy during the run-in period) 
• 
Loop diuretics at a dosage equivalent to 40 mg/day or more of furosemide tablet/fine granule 
• 
Concomitant administration of a loop diuretic and a thiazide diuretic (including similar drugs) 
at any doses 
• 
Concomitant administration of a loop diuretic and a mineralocorticoid receptor antagonist or 
potassium-sparing diuretic at any doses  
Note: The type and dosages of concomitant diuretics are specified as follows: 
c) Loop diuretics at a dosage equivalent to 40 mg/day or more of furosemide tablet/fine 
granule 
Bumetanide tablet, 1 mg; azosemide tablet, 60 mg; and torasemide tablet, 8 mg 
d) Thiazide diuretics (including similar drugs) 
Hydrochlorothiazide tablet, trichlormethiazide tablet, benzylhydrochlorothiazide tablet, 
and mefruside tablet 
e) Mineralocorticoid receptor antagonists or potassium-sparing diuretics 
Spironolactone tablet/fine granule and triamterene capsules 
3) 
Males or females between the ages of 18 and 89 years inclusive (at the time of informed consent) 
4) 
Subjects who were currently hospitalized or who are able to be hospitalized from the day before the 
run-in period (Day −4) until the end of the post-treatment examination (Day 16) 
5) 
Subjects who are able to take oral medications 
6) 
Subjects capable of providing written informed consent prior to the initiation of any trial-related 
procedures and capable, in the opinion of the investigator or subinvestigator, of complying with all 
the requirements of the trial. 
 
Rationale for Inclusion Criteria (Screening Period) 
1) Volume overload is manifested as lower limb edema, pulmonary congestion, and 
jugular venous distension and also as hepatomegaly and cardiac third sound, but 
lower limb edema, pulmonary congestion, and jugular venous distension are set as 
the criterion because they are less susceptible to other factors and were actually 
observed in many patients who participated in a phase 3 tolvaptan confirmatory 
trial in CHF subjects (156-06-002) and a clinical pharmacology trial in CHF 
subjects (Protocol No. 156-06-004). 
2) The criterion is set to select subjects who have volume overload despite having 
received diuretics other than vasopressin antagonists. 
3) The lower age limit is specified to select subjects who are legally competent to 
provide consent and the upper age limit is set at 89 years based on the fact that 
cardiac edema commonly affects the elderly and in consideration of subject 
safety. 
4) Subjects who are able to be hospitalized will be selected to ensure accurate 
evaluation and in consideration of subject safety. 
5) OPC-131461 used in the trial is a tablet formulation. 
6) The criterion is set to ensure ethically appropriate conduct of a clinical trial. 
 

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5.2.1.2 
Run-in Period 
Subjects who meet all of the following inclusion criteria (run-in period) will proceed to 
the treatment period. 
7) 
Subjects with lower limb edema, jugular venous distension (on Day −1 in the run-in period), or 
pulmonary congestion (by chest X-ray in the run-in period) 
8) 
Subjects who received diuretics without any change in the dose or regimen during the run-in period 
9) 
Subjects whose body weight changed by no more than 1.0 kg in 2 days before trial treatment begins 
(ie, between Day −2 and Day −1 in the run-in period) 
 
Rationale for Inclusion Criteria (Run-in Period) 
7) The criterion is set to select subjects with volume overload as these findings are 
commonly observed in patients with volume overload. 
8) The criterion is set to select subjects who have volume overload despite having 
received diuretics other than vasopressin antagonists. 
9) Volume overload needs to be stable to enable efficacy evaluation of OPC-131461. 
 
5.2.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria in the screening period will be 
excluded. 
1) 
Subjects with acute heart failure 
2) 
Subjects with an assisted circulation device 
3) 
Subjects with any of the following diseases, complications, or symptoms: 
• 
Suspected decrease in the circulating blood volume 
• 
Hypertrophic cardiomyopathy (other than the dilated phase) 
• 
Cardiac valve disease with significant valve stenosis 
• 
Hepatic encephalopathy with difficulty in adequate hydration 
4) 
Subjects with acute myocardial infarction occurred within 30 days before screening examination 
5) 
Subjects with confirmed active myocarditis or amyloid cardiomyopathy 
6) 
Subjects with any of the following diseases, complications, or symptoms: 
• 
Uncontrolled diabetes mellitus 
• 
Anuria 
• 
Urinary excretion disorders due to urinary stenosis, urinary calculus, tumor 
7) 
Subjects with any of the following medical histories: 
• 
Occurrence of sustained ventricular tachycardia or ventricular fibrillation within 30 days prior 
to screening examination in subjects not using an implantable cardioverter defibrillator 
• 
Occurrence of a cerebrovascular disorder within 6 months prior to screening examination 
(excluding asymptomatic cerebral infarction) 
• 
History of hypersensitivity or idiosyncratic reaction to benzazepines (tolvaptan sodium 
phosphate, tolvaptan, mozavaptan hydrochloride, and benazepril hydrochloride) 
8) 
Subjects who have undergone surgical gastrectomy or small intestine resection 

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9) 
Morbidly obese subjects with the body mass index (BMI = body weight [kg] / height [m]2) of more 
than 35 kg/m2 
10) Subjects with supine systolic blood pressure of less than 90 mmHg 
11) Subjects with any of the following clinical laboratory abnormalities: 
• 
Total bilirubin > 3.0 mg/dL 
• 
Serum creatinine > 3.0 mg/dL 
• 
Serum sodium < 125 mEq/L, serum sodium > 147 mEq/L 
• 
Serum potassium > 5.5 mEq/L 
12) Subjects with prior or concurrent hepatic impairment (including subjects with aspartate 
aminotransferase [AST] or alanine aminotransferase [ALT] greater than 3 times the upper limit of 
reference range at screening examination) 
13) (Removed due to deletion in Protocol Amendment 3) 
14) Subjects who cannot sense thirst or who have difficulty in ingesting water 
15) Females who are breastfeeding or have a positive pregnancy test before trial treatment begins 
16) Sexually active males of reproductive potential or sexually active females of childbearing potential 
who do not agree to practice 2 different methods of birth control or remain fully abstinent during 
the trial and for 90 days (males) or for 180 days (females) after the final administration of IMP. If 
employing birth control, 2 of the following methods must be used: vasectomy, tubal ligation, 
intrauterine device (IUD), birth control pill, and condom (all of these methods are approved or 
certified in Japan) 
17) Subjects who used any of the following drugs/foods/beverages/supplements at and after the 
specified time point 
 
Drug, Food, Beverage, Supplement 
Timing 
Vasopressin antagonists 
28 days before screening examination 
Drugs, foods, beverages, and supplements that may 
inhibit cytochrome P450 (CYP) 3A4 (see 
Table 10.4-1). 
However, topical agents that are allowed in 
Section 10.5 are excluded. 
4 days before IMP administration 
Drugs, foods, beverages, and supplements that may 
induce CYP3A4 (see Table 10.4-2). 
However, topical agents that are allowed in 
Section 10.5 are excluded. 
8 days before IMP administration 
Drugs that may inhibit or induce OATP1B1/3, 
MATE, OAT, or OCT (see Table 10.4-3 and 
Table 10.4-4). 
However, topical agents that are allowed in 
Section 10.5 are excluded. 
14 days before IMP administration 
Drugs that are CYP substrates and that, when used 
with OPC-131461, may or may possibly have 
reduced action (see Table 10.4-5). 
However, topical agents that are allowed in 
Section 10.5 are excluded. 
4 days before IMP administration 
Ensitrelvir 
11 days before IMP administration 
Drugs that are not approved in Japan, including 
IMPs other than OPC-131461 
30 days or 5 times the half-life of the 
drug, whichever is longer, before 
screening examination 
18) Subjects who, in the opinion of the investigator or subinvestigator, are inappropriate for inclusion 
in the trial for any other reason 
 

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Rationale for Exclusion Criteria 
1) Rapid symptom onset or worsening of symptoms may complicate the conduct of 
the trial. 
2) An assisted circulation device may affect efficacy and safety evaluations. 
3) Treatment that induces excessive diuresis may be unfavorable in such subjects. 
4) and 5) In consideration of safety. 
6) In consideration of safety and no adequate diuretic effect is expected in such 
subjects. 
7) In consideration of safety. 
8) This surgical history may affect efficacy and safety evaluations. 
9) Morbid obesity may complicate efficacy evaluation. 
10) Diuresis may decrease blood pressure. 
11) to 14) In consideration of safety. 
15) and 16) In consideration of general safety and ethical issues. 
17) These medications may affect efficacy and safety evaluations. 
18) In consideration of general safety and ethical issues. 
 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
If diet therapy (salt restriction) is used, the amount of salt in meals should not be changed 
from the start of the run-in period to the end of the post-treatment examination. For 
prohibited concomitant foods, beverages, and supplements, see Section 6.5.1. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
Consumption of caffeine, alcohol, and tobacco will be prohibited from the start of the 
run-in period to the end of the post-treatment examination. 
5.3.3 
Activity 
Not applicable. 
5.4 
Screen Failures 
A screen failure is a subject from whom informed consent is obtained and is documented 
in writing (ie, the subject signs an informed consent form [ICF]), but who is not 
randomized or assigned to the trial treatment(s). All AEs must be reported after subject 
informed consent has been obtained, including screening failures due to AEs, irrespective 
of IMP administration. 

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Subjects who sign an ICF but are not assigned to the trial treatment(s) may be rescreened 
once. If the screening examination is repeated, a new informed consent will be obtained, 
and a new subject ID number will be assigned beforehand. 
If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded in the source documents and eCRF: 
• Date of informed consent 
• Visit date (date of screening examination) 
• Demographics (collection date, birth date, sex, race, ethnicity, country where the trial 
was conducted) 
• Result of eligibility assessment 
• Screen failure date 
• Reason for screen failure 
• Adverse events 
 
6 
Trial Treatments 
The trial treatments in this trial are the IMPs (OPC-131461 tablets 1-mg and 5-mg) and 
matching placebo tablets. 
6.1 
Trial Treatments Administered 
The dose and drugs to use in each treatment group are shown in Table 6.1-1. 
The investigator or subinvestigator will orally administer 2 tablets of OPC-131461 tablet 
1-mg, OPC-131461 tablet 5-mg, or placebo tablet with water, immediately after 
completion of urination for urine volume measurement after breakfast once daily for 
14 days. The dosing time on and after Day 2 will be within 20 minutes before or after the 
dosing time on Day 1. Administration should be performed even if the subject does not 
have breakfast at all. 
After confirming that the subject has taken the drug completely, the date and time of 
administration, dose, presence/absence of breakfast, and time of completion of breakfast 
will be recorded in the source documents and eCRF. 
 

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Table 6.1-1 
Dose and Drugs to Use for Each Treatment Group 
Group Name 
Dose 
Drugs to Use 
OPC-131461 1-mg group 
1 mg/day 
OPC-131461 tablet 1-mg × 1, placebo tablet × 1 
OPC-131461 2-mg group 
2 mg/day 
OPC-131461 tablet 1-mg × 2 
OPC-131461 5-mg group 
5 mg/day 
OPC-131461 tablet 5-mg × 1, placebo tablet × 1 
OPC-131461 10-mg group 
10 mg/day 
OPC-131461 tablet 5-mg × 2 
Placebo group 
0 mg/day 
Placebo tablet × 2 
 
For the dosage regimen and treatment period (including the follow-up period after 
completion of IMP administration) for each treatment group, see Section 4.1. 
6.1.1 
Medical Devices 
Not applicable. 
6.2 
Management of Investigational Medicinal Product 
For full details on IMP management, please refer to the OPC-131461 IB and a separate 
procedure specifying the IMP management. 
6.2.1 
Packaging and Labeling 
Investigational medicinal product will be provided by the sponsor or designated agent to 
the IMP manager. The IMP will be supplied in packaging boxes. Each packaging box 
used in the dosing period will be labeled to clearly disclose the subject ID number, 
compound ID, trial number, sponsor’s name and address, route of administration, and 
appropriate precautionary statements. 
6.2.2 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP manager. 
The IMP will be stored according to the conditions indicated on the IMP label. 
The trial site staff will maintain a temperature log in the IMP storage area by recording 
the temperature. 
6.2.3 
Accountability 
The IMP manager must maintain an inventory record of IMP (investigational or placebo 
tablet) received, dispensed, administered, and returned. The IMP manager must not 
provide the IMP to any subject not participating in this trial. 

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6.2.4 
Returns and Destruction 
Upon completion or termination of the trial, unused IMP and partially-used IMP must be 
returned to the sponsor or a designated agent. All IMP returned to the sponsor must be 
accompanied by the appropriate documentation and be clearly identified by protocol 
number and trial site number on the outermost shipping container. Returned supplies 
should be in the original containers. The assigned trial monitor will facilitate the return of 
used IMP containers, unused IMP, and partially-used IMP. 
6.2.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) is any written, electronic, or oral communication 
provided by a healthcare professional, consumer, subject, medical representative, 
regulatory agency, Partner, or other third party that alleges deficiencies related to the 
identity, quality, durability, reliability, safety, effectiveness, or performance of a Medical 
Device or Medicinal Product or a falsified, tampered, or diverted product after it is 
released for distribution to a clinical trial. 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 or empty blisters) 
• Product defects (eg, odor, chipped, broken, embossing illegible) 
• Loss or theft of the product 
 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator/subinvestigator or designee must record each PQC 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) 
via e-mail (e-mail address: PQC_351-102-00004@otsuka.jp) or IWRS of the information 
described in Section 6.2.5.2 immediately after becoming aware of the PQC. 
Identification of a PQC by the subject should be reported to the site investigator or 
subinvestigator, who should then follow the reporting mechanism above. 

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6.2.5.2 
Information Required for Purposes of Reporting Product 
Quality Complaints 
• Description of complaint 
• Reporter identification (eg, subject, investigator/subinvestigator, site, etc.) 
• Reporter contact information (eg, address, phone number, e-mail address) 
• ID of material (product/compound name, IMP number) 
• Clinical protocol reference (number and/or trial name) 
• Dosage form/strength (if known) 
• Pictures of complaint sample (if available) 
• Availability of complaint sample for return 
 
6.2.5.3 
Return Process When Product Quality Complaints Are 
Received 
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the sponsor will provide return instructions, 
when applicable. 
It must be documented in the site accountability record that the complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
6.2.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
6.2.6 
Investigational Medicinal Product Reserve Sample Requirements 
Not applicable. 
6.3 
Measures to Minimize/Avoid Bias 
Subjects who meet the criteria for proceeding to the treatment period will be randomized 
at a ratio of 1:1:1:1:1 with the IWRS (placebo group: OPC-131461 1-mg group: 
OPC-131461 2-mg group: OPC-131461 5-mg group: OPC-131461 10-mg group). Details 
on treatment assignment to subjects will be shown in a separate written assignment 
confirmation. Neither the subjects nor the investigator/subinvestigator will be informed 
of the treatment assignment codes. Trial-related parties of the sponsor including contract 
research organizations (excluding bioanalytical laboratories and unblinded analytical 
organizations) will also be unaware of the treatment assignment codes. 
The indistinguishability of trial treatment will be confirmed by the allocation manager 
and the IMP packager prior to the start of the trial. A randomization table will be securely 
stored until unblinding after all eCRFs and databases have been locked. 

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Measurements of serum osmolality, plasma AVP concentration, urine osmolality, urine 
sodium concentration, and urine potassium concentration may unblind the trial 
treatments, while measurements of urine aquaporin 2 concentration may lead to an 
evaluation bias. Therefore, measurement results from laboratories will not be disclosed 
until unblinding. These measurements during the trial will be performed at specified 
laboratories, and will not be performed at local laboratories. 
Measurement of plasma drug concentration will be performed at a specific bioanalytical 
laboratory other than the trial site, and measurement results that can identify the subjects 
will not be disclosed to trial-related parties (excluding unblinded analytical organizations) 
until unblinding. When the sponsor receives the results of the PK analysis (descriptive 
statistics of the major PK parameters) from an unblinded analytical organization before 
unblinding, the results will not include individual data to keep the assigned trial 
treatments blinded. 
Procedures for breaking the blind are described in Section 8.8.7. 
6.4 
Subject Compliance 
The subjects will be under the control of the investigator or subinvestigator during the 
trial. The investigator or subinvestigator will instruct them to: 
• Administer the IMP and concomitant diuretics at the specified dose according to the 
specified dosage regimen; 
• Adhere to the prespecified schedule during the trial; 
• Never use the prohibited concomitant medications (see Section 6.5.1); 
• Never change the dose or dosage regimen of restricted concomitant medications (see 
Section 6.5.3); and, 
• Never disclose information obtained through participation in this trial to any third 
party. 
 
6.5 
Concomitant Medications and Therapies 
The investigator or subinvestigator will record all concomitant medications (including 
prescription medications, over-the-counter medications, herbal remedies, etc.) and other 
concomitant therapies from the date of signing a written informed consent until the end of 
the trial (defined as the date of last contact or the date of the final contact attempt) in the 
eCRF. 
For concomitant medications, the drug name, indication, dosage per administration, 
frequency, route of administration, and start and end dates of treatment will be recorded 

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in the eCRF. For concomitant therapies (including salt restriction), the name of the 
therapy, purpose, and start and end dates of treatment will be recorded in the eCRF. 
6.5.1 
Prohibited Medications and Therapies 
Use of the medications shown in Table 6.5.1-1 is prohibited during the period from each 
specified time point to the end of the post-treatment examination. 
 
Table 6.5.1-1 
List of Prohibited Medications 
No. 
Drugs, Foods, Beverages, and Supplements 
Timing 
1 
Vasopressin receptor antagonists 
28 days before the screening 
examination 
2 
The following therapeutic drugs (injections) for heart 
failure: 
a) Human atrial natriuretic peptide preparation 
b) Phosphodiesterase 3 inhibitor 
c) Catecholamine preparation 
d) Colforsin preparation 
Start of the run-in period 
3 
Diuretics (injections) 
4 
Drugs, foods, beverages, and supplements that may 
inhibit CYP3A4 (see Table 10.4-1). 
However, topical agents that are allowed in Section 10.5 
are excluded. 
4 days before IMP administration 
5 
Drugs, foods, beverages, and supplements that may 
induce CYP3A4 (See Table 10.4-2). 
However, topical agents that are allowed in Section 10.5 
are excluded. 
8 days before IMP administration 
6 
Drugs that may inhibit or induce organic anion 
transporter polypeptide (OATP) 1B1/3, multidrug and 
toxin extrusion (MATE), organic anion transporter 
(OAT), or organic cation transporter (OCT) (See 
Table 10.4-3 and Table 10.4-4). 
However, topical agents that are allowed in Section 10.5 
are excluded. 
14 days before IMP administration 
7 
Drugs that are CYP substrates and that, when used with 
OPC-131461, may or may possibly have reduced actions 
(See Table 10.4-5). 
However, topical agents that are allowed in Section 10.5 
are excluded. 
4 days before IMP administration 
8 
Ensitrelvir 
11 days before IMP administration 
9 
Drugs that are not approved in Japan, including IMPs 
other than OPC-131461 
30 days or 5 times the half-life of the 
drug, whichever is longer, before the 
screening examination 
 
Rationale for Prohibited Concomitant Medications 
No. 1 to No. 3 
These medications were selected because their use would make 
efficacy evaluation difficult. 

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No. 4 and No. 5 
OPC-131461 is metabolized by CYP3A4. Therefore, these 
medications were selected because drug interactions would make 
evaluation of the PK, safety, and efficacy difficult. 
No. 6 
Whether or not OPC-131461 has the potential to serve as a substrate of 
OATP1B1/3, MATE, OAT, and OCT has not been investigated, 
respectively. Therefore, these medications were selected because the 
possibility of drug interactions cannot be ruled out. 
No. 7 
These drugs were selected because OPC-131461 may induce the 
expression of the metabolic enzymes, or because the possibility of 
such induction cannot be ruled out. 
No. 8 
Ensitrelvir was selected because it is a potent CYP3A4 inhibitor and 
has a long half-life. 
No. 9 
These drugs were selected because they may affect the evaluation of 
efficacy and safety. 
 
6.5.2 
Medications Requiring Caution for Concomitant Use 
OPC-131461 may induce CYP3A4, and may also have the potential to induce CYPs 
other than CYP3A4. In addition, as its effect (inhibitory effect) on the transport activity 
of substrates of MATE1, MATE2-K, OAT1, OAT3, OCT2, and bile salt export pump 
(BSEP) has not been investigated, the possibility of drug interactions cannot be ruled out. 
Therefore, careful attention should be paid to the concomitant use of the medications 
listed in Table 10.6-1 between the start of IMP administration and the end of post-
treatment examination because such use may cause interactions. 
6.5.3 
Restricted Medications and Therapies 
The medications and therapies listed in Table 6.5.3-1 can be used concomitantly under 
the following conditions during the period from the run-in period to the end of the post-
treatment examination. 
1) The dose and dosage regimen of the medications listed in Table 6.5.3-1, which 
affect the status of volume overload and the conditions of the underlying disease, 
will not be changed. 
2) If diet therapy (salt restriction) is used, the amount of salt in meals will not be 
changed. 
 

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Table 6.5.3-1 
Restricted Medications and Therapies 
1) 
Diuretics other than vasopressin receptor antagonists (excluding eplerenone, esaxerenone, and 
finerenone) and SGLT2 inhibitors 
2) 
Infusion solution (except when used as a solvent for other drugs) 
3) 
Drugs intended to replace potassium 
4) 
Xanthines 
5) 
Nonsteroidal antiinflammatory drugs (excluding those used, as needed for local action; For drugs 
used for local action, refer to those permitted for concomitant use in Table 10.5.3-1.) 
6) 
Antihypertensives 
7) 
Therapeutic drugs for heart failure other than prohibited drugs 
 
Rationale for the Restricted Concomitant Medications 
1) to 7) These medications and therapies were selected to ensure that the diuretic effects 
of diet therapy (salt restriction) and drugs other than the IMP, as well as their effects on 
electrolyte concentrations in body fluids were suppressed to a certain level. Eplerenone, 
esaxerenone, and finerenone were selected as prohibited concomitant medications (see 
Table 10.4-5), because their effects may be reduced when OPC-131461 is used 
concomitantly. Therefore, these drugs are excluded from the restricted concomitant 
medications. 
 
6.5.4 
Rescue Medications 
Not applicable. 
6.6 
Intervention After the End of the Trial 
Not applicable. 
 

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7 
Stopping Rules, Withdrawal Criteria, and Procedures 
7.1 
Entire Trial or Treatment 
If the sponsor decides to terminate or suspend 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. 
7.2 
Individual Site 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the institutional review board (IRB) if judged to be necessary for medical, safety, 
regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
Good Clinical Practice (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. 
7.3 
Individual Subject Discontinuation 
7.3.1 
Treatment Interruption 
Not applicable. 
7.3.2 
Treatment Discontinuation 
After treatment assignment, 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. In any cases, 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 7.3.5. Subjects withdrawn from the trial after 
receiving the IMP will be encouraged to undergo all of the EOT/withdrawal examination, 
post-treatment examination, and follow-up examination. 
As per the protocol, subjects who terminate treatment before completing the 14 days of 
the treatment period because the investigator or subinvestigator judges that no further 
improvement of volume overload is necessary in a case that all congestive findings 
(lower limb edema, pulmonary congestion, jugular venous distension, hepatomegaly, 
pulmonary rales, or cardiac third sound) present at baseline are resolved or in other cases 
will undergo the EOT/withdrawal examination, post-treatment examination, and follow-
up examination at the specified timing following the final IMP administration of each 
early completer. 

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The EOT/withdrawal examination, post-treatment examination, and follow-up 
examination will be conducted in accordance with Section 1.3.17, Section 1.3.18, and 
Section 1.3.19, respectively. 
7.3.3 
Documenting Reasons for Treatment Discontinuation 
Every subject has the right to withdraw from the trial and the investigator or 
subinvestigator can also discontinue a subject’s participation in the trial at any time if 
medically necessary. In addition, subjects who meet any of the following criteria must be 
withdrawn from the trial. Only one main reason for discontinuation should be recorded in 
the eCRF. 
1) Adverse event-related reasons: 
• Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard 
• Continuing IMP places the subject at undue risk as determined by the investigator 
or subinvestigator (eg, a safety concern that is possibly, probably, or likely related 
to IMP) 
− SAE 
− Other potentially IMP-related safety concerns or AEs 
2) Withdrawal by subject 
3) Protocol deviation 
• Enrolled in the trial without meeting the inclusion criteria or with falling under 
the exclusion criteria 
• Continued to participate in the trial after falling under the withdrawal criteria 
during the trial 
• Inappropriate dose and/or regimen of IMP 
• Noncompliance with prohibited concomitant medications/therapies or restricted 
concomitant medications/therapies 
4) Protocol-specific withdrawal criterion met 
• Local or central clinical laboratory value (AST or ALT) ≥ 3 × upper limit of 
normal (ULN) 
• ≥ 12 mEq/L increase from baseline in local serum sodium concentration within 
24 hours after IMP administration 
• Local serum sodium concentration of ≥ 155 mEq/L during the treatment period 
*If these events are judged to be an AE, “adverse event” should be selected as the 
reason for discontinuation. 
5) Death 
6) Lost to follow-up 
7) Pregnancy (see Section 10.3) 
8) Study terminated by sponsor 

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9) Physician decision 
10) Other 
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. Follow-up procedures in Section 7.3.2 must be followed. 
7.3.4 
Withdrawal of Consent or Assent 
Each subject has the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects can withdraw consent for use of data which has 
not previously been anonymously transferred into trial data sets collected as part of the 
trial and can only withdraw consent 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: 
• Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by a home visit). 
• Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and trial site 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, 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 

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Section 7.3.2). A subject may, however, indicate that further trial participation is creating 
a burden on their work, school, or social schedule. Therefore, the investigator or 
subinvestigator should follow the procedures outlined in Section 7.3.3 to determine if the 
subject can continue participation in the trial if modifications to his/her treatment and/or 
schedule of assessments can be accommodated. Only subjects who withdraw their 
permission for all of the above methods of follow-up are considered to have completely 
withdrawn their consent to participate in the trial. 
Details on the withdrawal of consent from the optional Future Biospecimen Research 
(FBR) substudy are provided in the ICF for the FBR. 
7.3.5 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigators or 
subinvestigators will be instructed to meet and discuss (without undue coercion) with the 
subject their options of continuing in the trial, preferably on therapy. The investigator or 
subinvestigator should ensure understanding and documentation of the reasons for the 
subject’s desire to withdraw consent. 
7.4 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted before the last day of observation, 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 site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status. 
If the subject was classified as “lost to follow-up,” “Were you able to contact the 
subject?”, “Date of contact/Date of final contact attempt,” and “Contact method” will be 
recorded in the eCRF. 
 

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8 
Trial Procedures 
The assessments that are to be conducted during the trial are summarized in Table 1.3-1. 
8.1 
Efficacy Assessments 
8.1.1 
Body Weight 
The investigator or subinvestigator will instruct subjects to urinate at least once after 
waking up, and measure body weight before breakfast using an appropriately calibrated 
scale after minimizing the effects of bowel movements and variations due to clothes. The 
presence/absence of a measurement, the date and time of the measurement, and the 
measured value (up to the first decimal place in kg units) will be recorded in the source 
documents and eCRF. If measured to the second or further decimal place, the measured 
value will be rounded off to the first decimal place. 
8.1.2 
Congestive Findings (Lower Limb Edema, Jugular Venous 
Distension, Hepatomegaly, Pulmonary Rales, and Cardiac Third 
Sound) 
The investigator or subinvestigator will examine the subjects for congestive findings 
including lower limb edema, jugular venous distension, hepatomegaly, pulmonary rales, 
and cardiac third sound to assess the presence/absence and severity of each of the 
symptoms using the methods shown below. The presence/absence of an examination, 
date and time of the assessment, and results of the assessment will be recorded in the 
source documents and eCRF. 
1) Lower Limb Edema 
As a rule, the tibial margins or acrotarsia in a sitting position will be examined to 
assess the severity of edema according to the criteria in Table 8.1.2-1. 
 
Table 8.1.2-1 
Criteria for Assessment of Lower Limb Edema 
 
Severity 
Criteria for Assessment 
0 
Absent 
No pitting observed at all 
1 
Mild 
Slight pitting observed 
2 
Moderate 
Pitting observed 
3 
Severe 
Apparent edema 
 
2) Jugular Venous Distension 
The presence/absence of jugular venous distension will be investigated. For those 
in whom it is present, the height (cm) from the sternal angle to the highest point 
of pulsation of the internal jugular vein in a half-sitting position will be measured. 
The measured value will be recorded to one decimal place. 

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3) Hepatomegaly 
The presence/absence of liver palpable will be investigated. If palpable, its width 
(length [cm] from the costal arch on the right mammary gland line) will be 
measured. The measured value will be recorded to one decimal place. 
 
4) Pulmonary Rales 
The presence or absence of pulmonary rales will be investigated by auscultation. 
 
5) Cardiac Third Sound 
The presence or absence of cardiac third sound will be investigated by 
auscultation. 
 
8.1.3 
Chest X-ray (Cardiothoracic Ratio and Pulmonary Congestion) 
The investigator or subinvestigator will perform a chest X-ray, and record whether or not 
X-ray measurement is performed and date of chest X-ray in the source documents and 
eCRF. The cardiothoracic ratio and pulmonary congestion will be assessed using the 
methods shown below. 
1) Cardiothoracic Ratio 
The cardiothoracic ratio will be measured, and the measured value will be 
recorded in the source documents and eCRF. The measured value will be rounded 
to one decimal place for recording. 
 
2) Pulmonary Congestion 
The severity of pulmonary congestion will be determined according to the criteria 
in Table 8.1.3-1, and the determined severity will be recorded in the source 
documents and eCRF. 
 
Table 8.1.3-1 
Criteria for Assessment of Pulmonary Congestion 
 
Severity 
Criteria for Assessment 
0 
Absent 
No congestion 
1 
Mild 
Pulmonary venous congestion 
2 
Moderate 
Interstitial pulmonary edema 
3 
Severe 
Alveolar pulmonary edema 
These criteria were created by modifying the criteria in the following article: Medical therapy of acute 
myocardial infarction by application of hemodynamic subsets (First of two parts).5 
 

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8.1.4 
NYHA Functional Classification 
The investigator or subinvestigator will make an assessment using the NYHA Functional 
Classification (Table 8.1.4-1).1 The presence/absence of an assessment, date of 
assessment, and results of the assessment will be recorded in the source documents and 
eCRF. 
 
Table 8.1.4-1 
NYHA Functional Classification 
Functional Capacity 
Class I 
Patient has no limitation of physical activity due to heart disease. Ordinary physical 
activity does not cause fatigue, palpitations, dyspnea, or anginal pain. 
Class II 
Patient has slight limitation of physical activity due to heart disease, but comfortable in 
living his/her life with rest. Ordinary physical activity causes fatigue, palpitations, 
dyspnea, or anginal pain. 
Class III 
Patient has marked limitation of physical activity, but comfortable in living his/her life 
with rest. Less than ordinary activity causes fatigue, palpitations, dyspnea, or anginal 
pain. 
Class IV 
Patient is unable to carry on any physical activity without discomfort due to heart disease. 
Symptoms of heart failure or angina may be present, even at rest. Any physical activity 
worsens symptoms. 
 
8.2 
Pharmacokinetic Assessments 
8.2.1 
Pharmacokinetic Blood/Plasma Samples 
1) Blood Sampling Time Points 
Blood samples for PK assessments will be collected at the time points presented 
in the schedule of assessments (Table 1.3-1) and in the allowable time windows 
for postdose examinations/assessments (Table 1.3-2). The presence/absence of 
blood sampling and the date and time of blood sampling will be recorded in the 
source documents and eCRF. 
Vital sign measurements or ECG will be performed prior to blood sampling for 
PK assessments, when they are scheduled at the same time. 
 
2) Methods of Blood Sampling and Analysis 
Blood samples (2 mL) will be collected in vacutainers containing 
ethylenediaminetetraacetic acid (EDTA) and processed into plasma to measure 
concentrations of OPC-131461 and its metabolites (M35101 and M35103) by 
validated high performance liquid chromatography-tandem mass spectrometry. 
Analyses of metabolites not specified in the protocol may be performed, if 
necessary. Pharmacokinetic samples may be used for the investigation of a 
bioanalytical method, if needed. 
Plasma samples will be sent to the bioanalytical laboratory for analysis. The 
bioanalytical laboratory will measure the drug concentrations in samples from the 

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OPC-131461 groups only after recording the use of the randomization table. The 
contents of the randomization table should be strictly managed by the person 
responsible for measurement of drug concentrations, with no disclosure to any 
person other than those deemed necessary to execute the work. The results of drug 
concentration measurement will be securely stored by the bioanalytical 
laboratory. When electronic data on the results of drug concentration 
measurement are submitted to the sponsor before unblinding, information that can 
identify the subjects will be deleted beforehand. The bioanalytical laboratory will 
submit the electronic file containing the final data to the sponsor after unblinding. 
Recording the measurement results in the source documents or eCRF is not 
necessary. 
Details on collection, handling, and shipment of samples are provided in the 
procedures separately prepared. 
 
3) Rationale for the Blood Sampling Time Points 
Based on the population PK model using the results of the Japanese phase 1 single 
and multiple oral dose trial of OPC-131461 (351-102-00001), a simulation was 
performed to predict PK in patients with heart failure. As a result, it was found 
that the median tmax after single-dose treatment and 14-day multiple-dose 
treatment with OPC-131461 suspension was 4 hours and 3 hours, respectively, 
while the median t1/2,z after each of the treatments was 43.7 hours and 50.1 hours, 
respectively. 
To enable calculation of the necessary PK parameters after multiple doses, a total 
of 8 points including 1 point before IMP administration on Day 14, 3 points that 
are predicted to be around tmax of the unchanged drug (2, 4, and 6 hours after IMP 
administration), and 4 points that are predicted to be in the terminal elimination 
phase of the unchanged drug (8, 24, 32, and 48 hours after IMP administration) 
were set, taking into account the above results and feasibility. To investigate 
changes in plasma PK during multiple-dose treatment, blood samples will be 
collected at 6 points within 24 hours after each administration on Day 1 and 
Day 7, and at 1 point before administration on Day 12. To confirm that the blood 
concentration of unchanged drug has been decreased sufficiently, blood samples 
will also be collected at 1 point between Day 24 and Day 28 (between 240 and 
336 hours after IMP administration on Day 14). As a result, the number of blood 
sampling time points thus far is 22. Early completers will also undergo blood 
sampling at 3 points (24, 32, and 48 hours after the final IMP administration) and 
at 1 point in the follow-up examination (between 240 and 336 hours after the final 
IMP administration) for the purpose of confirming changes in plasma drug 
concentration after the end of IMP administration. 
 

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8.3 
Pharmacodynamic Assessments 
8.3.1 
Urine Volume 
8.3.1.1 
Urine Volume in a Time Point Set 
• Time points: Time points specified in the allowable time windows for the postdose 
examinations/assessments (Table 1.3-2) 
• Method: In the run-in period, urine volume will be measured at each of the time 
points shown in Table 1.3-2, setting the time after complete urination after breakfast 
as the starting time point. In the treatment period (after the start of IMP 
administration on Day 1), urine volume will be measured at each of the time points 
shown in Table 1.3-2, setting the time after complete urination after breakfast and by 
the time immediately before administration as the starting point. For the start time and 
end time of each time point, an allowable time window of  ± 30 minutes will be set. 
Subjects will be instructed to urinate completely at the end of each time point for the 
next urine accumulation. If urine volume in a time point set cannot be measured 
accurately for some reason (eg, some of urine samples have been discarded), the urine 
volume in the time point will not be measured and will be handled as missing data. 
The presence/absence of measurement, the start and end date and time of each time 
point, and urine volume in each time point will be recorded in the source documents 
and eCRF. 
 
8.3.1.2 
Daily Urine Volume 
• Time points: Every day from Day −3 in the run-in period to Day 16 in the post-
treatment observation period (2 days after the final IMP administration). However, 
the time points of measurement of urine volume in a time point set shown in 
Section 8.3.1.1 are excluded. 
• Method: Daily urine volume will be measured, setting the period from the time after 
complete urination after breakfast (or complete urination after breakfast and by the 
time immediately before administration in the treatment period) to the time after 
complete urination after breakfast (or complete urination after breakfast and by the 
time immediately before administration in the treatment period) on the next day as 
1 time point. If the daily urine volume cannot be measured accurately for some reason 
(eg, some of urine samples have been discarded), the daily urine volume on that day 
will not be measured and will instead be handled as missing data. The 
presence/absence of measurement, the start and end date and time of measurement, 
and the daily urine volume will be recorded in the source documents and eCRF. 
 
8.3.2 
Fluid Intake 
• Time points: Fluid intake will be measured using the same start and end time as those 
of each measurement time point shown in Section 8.3.1.1 and Section 8.3.1.2. 
• Method: The total amount of fluids contained in the specified meals and other fluids 
(beverages [juice, milk, tea, etc.], water, infusion solution, etc.) taken in each 

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specified interval will be measured. Fluid intake from the specified meals will be 
measured using the formula shown below. The water intake at the time of IMP 
administration will be included in the water intake after IMP administration. 
Formula: Fluid intake from the specified meals = fluid contained in the specified 
meals × food intake (proportion) 
• The presence/absence of measurement, the start and end date and time of 
measurement, and fluid intake in a time point set or daily fluid intake will be recorded 
in the source documents and eCRF. 
 
8.3.3 
Fluid Balance 
Fluid balance will be calculated using the following formula: Daily fluid intake − daily 
urine volume; or Fluid intake in a time point set − urine volume in a time point set. Fluid 
balance will be calculated by the sponsor, and therefore, recording in the eCRF is not 
necessary. 
8.3.4 
Clinical Laboratory Tests for Pharmacodynamic Assessments 
The samples listed in Table 8.3.4-1 will be collected at the time points presented in the 
schedule of assessments in Table 1.3-1. The presence/absence of measurement, the date 
and time of blood sampling, and the date and time of urine collection will be recorded in 
the source documents and eCRF. As for serum electrolyte (sodium, potassium) 
concentrations and serum creatinine concentrations, data obtained from a clinical 
laboratory test will be used if the time point of blood sampling for measurement is the 
same as the time point specified in Section 8.7.1. Details on collection, handling, and 
shipment of samples are provided in the procedures separately prepared. If urine volume 
in a time point set or daily urine volume cannot be measured accurately for some reason 
(eg, some of urine samples have been discarded), the urine electrolyte concentration, 
urine osmolality, and urine aquaporin 2 concentration in the time point or on the day will 
be handled as missing data without sending the samples to the laboratory. 
All samples for central measurement will be sent to the central laboratory. Central 
measurements will be performed according to the procedure specified by the laboratory, 
and their results will be reported to the sponsor and investigator/subinvestigator. The 
electronic file containing the measurement results provided to the sponsor from the 
central laboratory will be used as a source document; therefore, recording in the eCRF is 
not necessary. To maintain blindness, the results of measurements of serum osmolality, 
plasma AVP concentration, urine osmolality, and urine electrolyte (sodium, potassium) 
concentrations will be kept undisclosed until unblinding at the end of the trial. The results 
of measurements of urine aquaporin 2 concentration will also be kept undisclosed until 
unblinding at the end of the trial, because an evaluation bias may occur. The 

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measurement results will be securely stored by the laboratory, reported to the investigator 
or subinvestigator after unblinding, and provided to the sponsor in an electronic file. 
In order that the investigator or subinvestigator can quickly grasp the state of serum 
sodium and potassium concentration for subject safety, serum sodium and potassium 
concentrations will also be measured at each trial site during the treatment period, and the 
presence/absence of blood sampling, the date and time of blood sampling, and the 
measurement results will be recorded in the source documents and eCRF. If a local 
measurement of serum potassium concentration is found to exceed 5.5 mEq/L, a 12-lead 
ECG will be performed with reference to Section 8.7.4. 
Daily urine sodium excretion or daily urine potassium excretion will be calculated by 
multiplying the urine sodium concentration or urine potassium concentration by the daily 
urine volume. Urine excretion will be calculated by the sponsor, and therefore, recording 
in the eCRF is not necessary. 
 
Table 8.3.4-1 
Pharmacodynamic Clinical Laboratory Assessments 
Urine: 
Urine osmolality 
Urine electrolyte (sodium, potassium) 
concentrations 
Urine aquaporin 2 concentration 
Serum: 
Serum osmolality 
Serum electrolyte (sodium, potassium) 
concentrations 
Serum cystatin C concentration 
Serum creatinine concentration 
Serum troponin I concentration 
Serum NT-proBNP concentration 
 
Plasma: 
Plasma AVP concentration 
Plasma renin activity 
Plasma aldosterone concentration 
Plasma BNP concentration 
 
8.4 
Pharmacogenomic Assessments 
Not applicable. 
8.5 
Exploratory Assessments 
8.5.1 
Carbohydrate Antigen 125 (CA125) 
Samples for CA125 assessment will be collected at the time points presented in the 
schedule of assessments (Table 1.3-1), and the presence/absence of blood sampling and 
the date and time of blood sampling will be recorded in the source documents and eCRF. 
For females of childbearing potential (FOCBP), information on a menstrual cycle (the 

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start and end date of the most recent menstrual cycle, and the length of a menstrual cycle) 
and the presence/absence of menstruation at the time of sample collection will be 
obtained by interview, and recorded in the source documents and eCRF. If subjects 
menstruate on Day 1, blood sampling for CA125 measurement and subsequent tests are 
not necessary. If subjects menstruate on a sampling day other than Day 1, blood sampling 
for CA125 on the day is not necessary. 
Details on collection, handling, and shipping of samples are provided in the procedures 
separately prepared. All samples will be sent to the central laboratory. Central 
measurements will be performed according to the procedure specified by the laboratory, 
and their results will be reported to the sponsor and investigator/subinvestigator. The 
electronic file submitted from the laboratory to the sponsor will be used as a source 
document. Thus, recording the measurement results in the eCRF is not necessary. 
8.5.2 
Echocardiography for LVEF 
Echocardiography (disc method [modified Simpson method]) will be performed to 
measure LVEDV, LVESV, and LVEF at the time points presented in the schedule of 
assessments (Table 1.3-1). Whenever possible, the measurements should be performed by 
the same examiner. The date of echocardiography and the measurements (to one decimal 
place) will be recorded in the source documents and eCRF. Values measured to more 
than one decimal place will be rounded to one decimal place. Echocardiography will not 
be required if measurement cannot be performed at a trial site due to problems securing a 
reservation for the use of measuring equipment or availability of measurement with the 
disc method (modified Simpson method). 
8.6 
Future Biospecimen Research Samples 
Deoxyribonucleic acid (DNA) samples will be stored to enable future exploratory 
investigations of variations in DNA characteristics related to individual differences in 
drug responses (eg, efficacy, safety, or PK) to the IMP and/or disease-related variations 
in DNA characteristics, or for use in basic research for development with the goal of 
treating disease or promoting health. 
In addition, plasma and urine will be stored as biomarker samples to enable future 
exploratory investigation of biomarkers related to drug responses (efficacy or safety) to 
the IMP or diseases. 
 

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Rationale for Sample Storage for Future Biospecimen Research 
DNA samples will be stored so that genomic/genetic analysis can be performed if further 
explanation is required about the PK of the IMP, if new information on genes and PK 
becomes available, if genomic/genetic analysis in relation to drug responses (efficacy or 
safety) to the IMP is determined to be useful, and/or if genomic/genetic analysis is 
determined to be useful as basic research for development with a goal of treating disease 
or promoting health. With regard to collecting and storing DNA samples during a clinical 
trial, the Ministry of Health, Labour and Welfare (MHLW) states, in Q&A 1 in 
“Regarding Clinical Studies Utilizing Pharmacogenomics (PFSB/ELD Notification No. 
0930007 dated 30 Sep 2008),” that it is possible to collect samples from subjects to 
perform genomic/genetic analyses relevant to evaluation (PK, efficacy, safety, etc.) of an 
IMP in a clinical trial, in either of following cases: (1) if the target and time of 
genomic/genetic analyses have been determined at the time of the trial or (2) if the target 
and time of genomic/genetic analyses have yet to be determined at the time of the trial 
but such analyses related to IMP evaluation may be considered in the future. The MHLW 
also states in Q&A 2 that it is possible to collect samples from subjects for 
genomic/genetic analyses irrelevant to evaluation of an IMP.6 The International Council 
for Harmonisation (ICH) also states, in Section 1.4 General Principles in the Guidelines 
on Genomic Sampling and Management of Genomic Data E18 as follows: “With 
advances in science and increased awareness of the impact of genomics, there is a need 
and an opportunity to maximize the value of the collected samples and the data generated 
from them. Therefore, genomic sample acquisition is strongly encouraged in all phases 
and studies of clinical development.”7 
Biomarker research is expected to enhance the productivity of research and development 
of pharmaceutical products. 
In addition to the above, as this trial is designed to reduce the burden on subjects as much 
as possible by timing sample collection to coincide with the time point for another 
examination, optional collection and storage of samples for Future Biospecimen Research 
(FBR) is justified. 
8.6.1 
Scope of Future Biospecimen Research 
Future Biospecimen Research samples will be collected from subjects who voluntarily 
consent to this sample collection. Research performed on these samples may include 
genetic analyses (DNA) and biomarker analyses (plasma and urine) such as proteomics 
and metabolomics. Such research is for biomarker testing to address emergent questions 
not described elsewhere in the protocol (as part of the main trial), and will only be 

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conducted on specimens from subjects who have provided appropriate consent. The 
objective of collecting specimens for FBR is to explore and identify biomarkers that 
inform the scientific understanding of various diseases and/or their therapeutic treatments 
as well as health promotion. 
8.6.2 
Summary of Procedures for Future Biospecimen Research 
Samples 
All subjects enrolled in the clinical trial will be considered for enrollment in the optional 
FBR substudy. After informed consent is obtained, the following FBR samples will be 
collected at the time points presented in the schedule of assessments (Table 1.3-1) and the 
allowable time windows for postdose examinations/assessments (Table 1.3-2). 
• Blood (2 mL, EDTA as anticoagulant) for DNA analysis 
• Blood (3 mL, EDTA as anticoagulant) to prepare plasma for biomarker analysis 
• Spot urine (approximately 11 mL) for biomarker analysis 
A portion of the spot urine will be used for a protein quantitative test. 
Before IMP administration on Day 1, the results of the protein qualitative test in the 
laboratory test will be used, and a protein qualitative test will not be required. 
For DNA samples, the presence/absence of blood sampling and date of blood sampling 
will be recorded in the source documents and eCRF. For biomarker samples, the date and 
time of IMP administration immediately before sample collection, the presence/absence 
of sample collection, the date and time of blood sampling, the date and time of urine 
collection, and the presence/absence of a protein quantitative test will be recorded in the 
source documents and eCRF. For the results of the protein quantitative test, the electronic 
file submitted from the laboratory to the sponsor will be used as a source document, and 
recording in the eCRF is not necessary. Details on collection, handling, and shipment of 
samples are provided in the procedures separately prepared. If a FBR substudy is 
planned, a separate document describing the analysis may be prepared and the results 
may be reported separately from the clinical study report. 
8.6.3 
Retention of Future Biospecimen Research Samples 
The DNA samples will be stored at the biorepository for potential analysis until: 
1) genomic/genetic analysis is determined to be no longer necessary, 2) 15 years have 
passed since the first informed consent for DNA storage was obtained in this trial, or 
3) the subject withdraws his/her consent to participate in DNA sample storage, whichever 
comes first. 
The biomarker samples will be stored at Otsuka Pharmaceutical Co., Ltd. or its contract 
organization for potential analysis until: 1) biomarker analysis is determined to be no 

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longer necessary, 2) 15 years have passed since the end of the trial, or 3) the subject 
withdraws his/her consent to participate in biomarker sample storage, whichever comes 
first. 
8.6.4 
Genomic/Genetic Analysis 
Genomic/genetic analysis for exploratory investigation of variations in DNA 
characteristics related to individual differences in drug responses (eg, efficacy, safety, 
PK) to the IMP and/or disease-associated variations in DNA characteristics or as basic 
research for development with a goal of treating disease or promoting health will be 
performed only if the analysis is determined to be useful. 
Once genomic/genetic analysis is determined to be performed, a pharmacogenomic study 
protocol will be prepared and approved by the sponsor’s research review board, and 
analysis will then be performed in compliance with the applicable national laws and 
regulations. 
The target of genomic/genetic analysis cannot be identified at present, and genome-wide 
analyses with DNA chips, microarrays, or next-generation sequencer may be performed. 
In any case, the results of the analysis will not be used for other purposes than those 
mentioned above. 
DNA samples for genomic/genetic analysis will be double-coded by the biorepository 
and shipped to the genomic/genetic analysis facility (yet to be designated), which will 
then perform genomic/genetic analysis with the double coding maintained. 
8.6.5 
Biomarker Analysis 
A biomarker analysis for exploratory investigation of biomarkers related to drug 
responses (efficacy or safety) to the IMP or diseases will be performed only if the 
analysis is determined to be useful. 
Once biomarker analysis is determined to be performed, a separate protocol will be 
prepared and approved by the sponsor’s research review board, and analysis will then be 
performed in compliance with the applicable national laws and regulations. 
The substances to be measured and analyzed cannot be identified at present, and a wide 
range of components in plasma or urine may be analyzed. In any case, the results of the 
analysis will not be used for purposes other than those mentioned above. 

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8.6.6 
Informed Consent for Participation in Future Biospecimen 
Research and Withdrawal of Consent 
An ICF on FBR sample storage and possible analysis on FBR samples will be prepared 
separately from the ICF for the main trial, and a signed ICF to participate in FBR will be 
obtained from the subject. The date of consent will be recorded in the source documents 
and eCRF. 
If a subject withdraws consent for FBR sample storage during the storage period, the 
sponsor will request the organization retaining the samples to discard the samples of the 
subject in question, and the organization retaining the samples will dispose of the samples 
in such a way that the subject cannot be identified. However, if individual samples cannot 
be identified because information connecting samples with subject identification (eg, 
code list) has already been destroyed or for other reasons, disposal of samples from a 
subject who withdraws consent may be impossible. 
Even if a subject decides to discontinue participation in the clinical trial, participation in 
FBR sample storage will not be canceled automatically. If the results of analysis have 
been obtained at the time of consent withdrawal, the results will not be discarded. 
8.6.7 
Disclosure of Analysis Results to Subjects 
Any findings from genomic/genetic analysis and biomarker analysis will be of an 
exploratory nature or still in the early stage of research, and their scientific reliability in 
terms of precision or certainty will not have been firmly established. Since it would not 
be of benefit to the subject to disclose information that has not been verified to be 
scientifically reliable, the sponsor will not disclose the analysis results to the subject, in 
principle. 
8.7 
Safety Assessments 
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8. 
8.7.1 
Clinical Laboratory Assessments 
Clinical laboratory samples will be collected at the time points described in the schedule 
of assessments (Table 1.3-1) to perform the clinical laboratory assessments described in 
Section 10.2. The total volume of blood to be collected during the trial will be 
documented in the ICF. 
All samples for central measurement will be sent to the central laboratory. Details on 
collection, handling, and shipping of samples are provided in the procedures separately 

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prepared. Central measurements will be performed according to the procedure specified 
by the laboratory, and their results will be reported to the sponsor and 
investigator/subinvestigator. The presence/absence of blood sampling/urine collection 
and the date and time of blood sampling/urine collection will be recorded in the source 
documents and eCRF. The electronic file containing the measurement results provided to 
the sponsor from the central laboratory will be used as a source document; therefore, 
recording in the eCRF is not necessary. 
In order that the investigator or subinvestigator can quickly grasp the state of serum 
sodium and potassium concentration for subject safety, serum sodium and potassium 
concentrations will also be measured at each trial site during the treatment period, and the 
presence/absence of blood sampling, the date and time of blood sampling, and the 
measurement results will be recorded in the source documents and eCRF. If a local 
measurement of serum potassium concentration is found to exceed 5.5 mEq/L, a 12-lead 
ECG will be performed with reference to Section 8.7.4. 
For FOCBP, a pregnancy test will be performed at the time of the screening examination 
with reference to Section 10.3, and the results must be obtained before IMP 
administration. A urine human chorionic gonadotropin (hCG) test will be performed 
using a pregnancy diagnostic reagent provided by the sponsor. If the result is unclear, a 
urine hCG test will be performed again. If the result of the urine test is positive, the 
investigator or subinvestigator will perform a serum test for confirmation. The 
investigator or subinvestigator will confirm the test result and record the 
presence/absence of a test, the date of the test, and the result of the test (positive or 
negative) in the source documents and eCRF. 
8.7.2 
Physical Examination 
Physical examinations will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). 
Physical examinations include assessment of the head, ears, eyes, nose, pharynx, chest, 
abdomen, genitourinary tract, extremities, nerves, and skin and mucosae. 
At screening, the presence/absence, date, and results of assessment will be recorded in the 
eCRF. At subsequent time points, the presence/absence and date of assessment only will 
be recorded in the eCRF and the results of assessment will be recorded in the source 
documents only. Any clinically significant physical finding not observed at screening but 
observed later will be recorded as an AE in the eCRF. 

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The investigator or subinvestigator will bear primary responsibility for the assessment of 
physical examination findings. Whenever possible, the same person will assess the 
physical examination findings of an individual subject throughout the course of the trial. 
8.7.3 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) will 
be collected at the time points described in the schedule of assessments (Table 1.3-1). 
Subjects should be monitored for clinically significant vital sign values. 
After a rest of at least 3 minutes, axillary temperature will be measured, after which 
systolic blood pressure, diastolic blood pressure, and pulse rate will be measured in a 
supine position, according to the methods specified by the trial site. Body temperature 
should be recorded to one decimal place. Values measured to more than one decimal 
place will be rounded to one decimal place. The presence/absence of measurement, the 
date and time of measurement, and the results of measurement will be recorded in the 
source documents and eCRF. 
8.7.4 
Electrocardiography 
Electrocardiography will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). Subjects should be monitored for clinically significant ECG 
findings. 
A 12-lead electrocardiograph provided by the central ECG measurement facility will be 
used to measure resting 12-lead ECGs, according to the method specified by the central 
ECG measurement facility. The investigator or subinvestigator will assess the 
measurement result as either normal or abnormal and record the presence/absence of 
assessment, the date of ECG, and the result of the assessment (normal or abnormal; and if 
abnormal, the abnormal findings) in the source documents and eCRF. If a local 
measurement of serum potassium concentration is found to exceed 5.5 mEq/L on any day 
in the treatment period when a 12-lead ECG is not scheduled in the protocol, then an 
additional 12-lead ECG will be performed as an unscheduled examination. 
The record of the ECGs measured using the 12-lead electrocardiograph provided by the 
central ECG measurement facility will be sent to the central ECG measurement facility 
for measurement of heart rate, PR interval, RR interval, QRS interval, QT interval, and 
QTc interval (QTcB and QTcF). The central ECG measurement facility will send a 
12-lead ECG measurement report to the investigator or subinvestigator. 

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The investigator or subinvestigator will reconfirm the result of the 12-lead ECG 
assessment with reference to the 12-lead ECG measurement report, and sign and store the 
report. 
The electronic file containing the 12-lead ECG measurement report submitted from the 
central ECG measurement facility to the sponsor will be used as a source document. 
Recording the heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc 
interval (QTcB, and QTcF) in the eCRF is not necessary. 
8.7.5 
Suicidality Monitoring 
Not applicable. 
8.7.6 
Other Safety Variables 
Not applicable. 
8.8 
Adverse Events 
8.8.1 
Definitions 
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered a drug used in the clinical trial and which does not necessarily have a causal 
relationship with this treatment. In this trial, any untoward medical occurrence in a 
subject not administered a drug used in the clinical trial is also deemed as an AE. 
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 a 
drug used in the clinical trial, related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug used in the clinical trial caused the AE. 
There are 2 different definitions of an adverse reaction: One is an adverse reaction to a 
drug used in the clinical trial that should be reported by the investigator as specified in 
Article 48 of the GCP and the other is an adverse reaction to the IMP as an endpoint in 
the trial. This section refers to the former definition. 
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of double-blind treatment. In more detail, TEAEs are all AEs that started after the 
start of double-blind IMP treatment, or are continuous from baseline and worsen. 

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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 inpatient hospitalization or prolongs hospitalization. 
− Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported. Note that hospitalization is 
an outcome of some event, and, therefore, the reason for the hospitalization 
should be reported whenever possible. In the event the reason is not known, 
the event of hospitalization should still be reported as an SAE. 
− Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not 
considered SAEs. 
− Prescheduled hospitalization to address a condition that has existed prior to 
the signing of the ICF should not be considered an SAE. 
• Congenital anomaly/birth defect. 
• Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse. 
 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
Adverse Events of Special Interest (AESIs): A noteworthy event for the particular 
product/IMP or class of products that a sponsor may wish to monitor carefully. All AESIs 
are to be reported as IREs. No AESIs have been identified for the IMP to be administered 
during this trial. 
Immediately Reportable Event (IRE): 
• Any SAE. 
• Any AE related to occupational exposure. 
• Potential serious hepatotoxicity (see Section 8.8.6). 
• 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 and the 
Pregnancy Surveillance Form(s) to the sponsor. This includes pregnancy of the 

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subject or the partner of the subject. Pregnancy will only be documented on the 
AE eCRF if the pregnancy occurs in a female subject and there is an abnormality 
or complication.  
 
Clinical Laboratory Test Value Changes: It is the investigator’s or subinvestigator’s 
responsibility to review the results of laboratory tests for each individual subject as they 
become available. This review will be documented by the investigator/subinvestigator’s 
dated signature on the laboratory report. The investigator or subinvestigator may repeat 
the laboratory test or request additional tests to verify the results of the original laboratory 
tests. If the laboratory value is considered medically relevant (ie, clinically significant) 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, it is considered an AE. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated in 
the eCRF. The severity 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. 
8.8.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will regularly assess or examine subjects for the 
occurrence of AEs. To avoid bias in eliciting AEs, subjects should be asked the 
nonleading 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 eCRF 
provided by the sponsor. Adverse event collection will begin after a subject signs the 
ICF, and will continue until the end of follow-up. All AEs must be recorded in the eCRF 
after subject informed consent has been obtained, including screening failures due to 
AEs, irrespective of trial intervention administration. 

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Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms. 
Exacerbation or disease progression should be reported as an AE only if there are 
unusual or severe clinical features that were not present, or experienced earlier, or not 
expected based on the course of the condition. A reported AE that worsened in severity or 
seriousness should be reported as a new AE in the eCRF. 
In addition, the sponsor must be notified immediately by e-mail, in principle, of any IREs 
according to the procedure outlined below, in Section 8.8.3. Special attention should be 
paid to recording hospitalization and concomitant medications. 
The AE, start date, end date (or start date and time and end date and time if the subject is 
hospitalized), seriousness, severity, relationship to trial treatment (IMP causality), action 
taken with trial treatment, and outcome will be recorded on the source documents and in 
the eCRF. When an SAE is reported using an IRE form or other methods, any drugs other 
than the IMP used in the clinical trial will also be assessed in terms of relationship to and 
action taken with treatment with the drugs, as with the IMP, and will be recorded on the 
source documents. 
Note: For AEs occurring during hospitalization, time will also be recorded if possible. If 
the exact time of onset/resolution is unknown (cannot be identified in minutes), time in 
terms of hours will be identified. Particular attention should be paid to determination of 
the time of onset and resolution of vomiting during hospitalization to provide a basis for 
considering the extent of IMP absorption. 
8.8.3 
Immediately Reportable Events 
The investigator or subinvestigator must immediately report (within 24 hours), using an 
IRE form, after he/she or site personnel become aware of any IRE (SAE, AE related to 
occupational exposure, AESI, potential serious hepatotoxicity, or confirmed pregnancy), 
by e-mail in principle to the sponsor or designee using the contact information on the 
cover page of this protocol (please note that the IRE form is NOT the AE eCRF). Patient 
confidentiality must be protected and contact information such as name, address, phone 
number or any other protected health information as determined by applicable local 
regulation must be redacted when forwarding Safety Information and supporting 
documentation. Details regarding the follow-up of IREs are included in Section 8.8.8.2 
8.8.4 
Medical Device Incidents (Including Malfunctions) 
Not applicable. 

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8.8.5 
Adverse Events of Special Interest 
Not applicable. 
8.8.6 
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 in the eCRF. 
8.8.7 
Procedure for Breaking the Blind 
In the event that an SAE or other significant event occurs and the investigator or 
subinvestigator decides that the emergency code needs to be opened to ensure subject 
safety, the investigator or subinvestigator may obtain the emergency code through IWRS 
according to the separately specified procedure. 
The investigator or subinvestigator is encouraged to contact the sponsor/Clinical 
Research Organization (CRO) medical advisor to discuss their rationale for unblinding. 
However, to prevent delays to the investigator/subinvestigator or medical personnel 
responding to a potentially emergent situation, unblinding of IMP will not be dependent 
upon the investigator or subinvestigator receiving approval from the sponsor/CRO 
medical advisor (ie, the investigator or subinvestigator will be able to obtain the code 
break information independent of the sponsor/CRO medical advisor). The investigator or 
subinvestigator must contact the sponsor/CRO medical advisor by telephone or e-mail 
with an explanation of the need for opening the treatment assignment code within 
24 hours of opening the code. If the blind is broken, the Office of Pharmacovigilance 
Operations, Department of Pharmacovigilance 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. 
8.8.8 
Follow-up of Adverse Events 
8.8.8.1 
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 in the eCRF. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 

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to further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history, and occupation). 
8.8.8.2 
Follow-up of Immediately Reportable Events 
This trial requires that subjects be actively monitored for IREs up to 10 to 14 days after 
the last dose of IMP is administered. 
Immediately reportable events that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eCRF page and the IRE form. If updated 
information (eg, resolved status) on IRE status becomes available after a subject’s last 
scheduled contact (up to last in-clinic visit for the entire trial), this must be reported to the 
sponsor and recorded on the AE eCRF page and the IRE form, according to the 
appropriate reporting procedures described in Section 8.8.3. 
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. The investigator or subinvestigator will follow IREs until the events are: 
• Resolved, 
• Stabilized, 
• The subject is lost to follow-up, or 
• Has died. 
 
Resolution means that the subject has returned to the baseline state of health and 
stabilized means that the investigator or subinvestigator does not expect any further 
improvement or worsening of the subject’s condition. The investigator or subinvestigator 
will continue to report any significant follow-up information to the sponsor up to the 
point the event has resolved or stabilized, or the subject is lost to follow-up, or has died. 
Refer to Section 10.3 for additional information regarding the follow-up period for 
subjects that become pregnant or for pregnant partners of male subjects. 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring after Last Scheduled Contact 
Any new IREs reported to the investigator or subinvestigator which occur after the last 
scheduled contact and are determined by the investigator or subinvestigator to be 
reasonably associated with the use of the drug used in the clinical trial, should be reported 
to the sponsor according to the procedures outlined in Section 8.8.3. This may include 
IREs that are captured on follow-up telephone contact or at any other time point after the 
defined trial period and continue to report any significant follow-up information to the 

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sponsor until the events are resolved or stabilized, or the subject is lost to follow-up or 
has died. 
8.9 
Treatment of Overdose 
For treatment of overdoses, please refer to Section 6.4 in the IB for OPC-131461. 
8.10 
Subject Assessment Recording 
Not applicable. 
8.11 
Other Assessments 
Not applicable. 
 
9 
Statistical Considerations 
9.1 
Sample Size 
The sample size is set as 31 subjects per group. 
Assuming that a dose of OPC-131461 5 mg or higher is equivalent to that of tolvaptan 
15 mg in patients with CHF, the sample size required to demonstrate the superiority of 
OPC-131461 over placebo in terms of the primary endpoint, ie, the change in body 
weight from baseline to the last assessment time point (the day after IMP administration) 
by Day 8, was determined (multiplicity relating to the use of more than one OPC-131461 
dose group was not considered). 
The results of the phase 3 confirmatory trial of tolvaptan (Protocol 156-06-002; placebo-
controlled 7-day treatment) demonstrated that the change from baseline in body weight 
on the day after the final IMP administration (LOCF) was −0.45 ± 0.93 kg 
(mean ± standard deviation [hereinafter, the same applies]) for the placebo group and 
−1.54 ± 1.61 kg for the tolvaptan 15-mg group. Based on these results, assuming a 
treatment difference of −1.09, standard deviation (combined) of 1.30, statistical power of 
90%, and two-sided significance level of 5%, the sample size required is set as 
31 subjects per group for a total of 155 subjects. 
9.2 
Datasets for Analysis 
The full analysis set includes all subjects who have been administered at least one 
treatment of the IMP, and for whom efficacy data after IMP administration are available. 
The safety analysis set includes all subjects who have been administered at least one 
treatment of the IMP. 

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The PK analysis set includes all subjects who have been administered at least one 
treatment of OPC-131461 and have at least one measurement of plasma drug 
concentration. 
The PD analysis set includes all subjects who have been administered at least one 
treatment of the IMP and have evaluable PD data after IMP administration. 
9.3 
Handling of Missing Data for Primary and Secondary Endpoint 
Analysis 
For missing values, no imputation will be applied. 
9.4 
Statistical Analyses 
9.4.1 
Efficacy Analyses 
The following analyses will be performed using the full analysis set. 
9.4.1.1 
Primary Efficacy Endpoint Analysis 
The primary endpoint is the change in body weight from baseline (before IMP 
administration on Day 1) to the last assessment time point (the day after IMP 
administration) by Day 8. 
For the primary analysis, an analysis of covariance model with treatment group as a fixed 
effect and baseline body weight as a covariate will be used. Comparisons between each 
OPC-131461 dose group and the placebo group will be performed at a two-sided 
significance level of 5%, and the difference in the least squares means between the 
treatment groups and the two-sided 95% CIs will be determined. 
In addition, to investigate the dose-response relationships for placebo, 1, 2, 5, and 10 mg, 
the above-mentioned model will be used to contrast the response saturated at 1 mg, 
response saturated at 2 mg, response saturated at 5 mg, and linear response. 
9.4.1.2 
Key Secondary Efficacy Endpoint Analysis 
Not applicable. 
9.4.1.3 
Secondary Efficacy Endpoint Analysis 
For the change in body weight from baseline (before IMP administration on Day 1) to the 
last assessment time point (the day after IMP administration) by Day 15, an analysis will 
be performed in the same manner as the primary endpoint analysis. 
For the percent changes in body weight from baseline to the last assessment time point 
(the day after IMP administration) by Day 8 and to the last assessment time point (the day 
after IMP administration) by Day 15, descriptive statistics will be calculated. 

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For lower limb edema and pulmonary congestion, improvement rates (percentages of 
subjects who have symptoms at baseline and show markedly improved or improved after 
IMP administration [improvement grading is as per Table 9.4-1]) and resolution rates 
(percentages of subjects who have symptoms at baseline and no symptoms after IMP 
administration) at the last assessment time point (the day of IMP administration) by 
Day 7 and the last assessment time point (the day after IMP administration) by Day 15, 
and their two-sided 95% CIs will be determined for each group. Fisher’s exact test will be 
used to compare each OPC-131461 dose group and the placebo group. 
 
Table 9.4-1 
Improvement Grading for Lower Limb Edema and 
Pulmonary Congestion 
 
Improvement Grading 
Criteria for Assessment 
1 
Markedly improved 
Symptom resolution or improvement by at least 2 grades 
2 
Improved 
Improvement by 1 grade (symptom resolution will be assessed as 
markedly improved) 
3 
Unchanged 
No change in the severity of symptoms/no symptoms throughout the 
trial period 
4 
Worsened 
Worsening by at least 1 grade 
 
For pulmonary rales and cardiac third sound, resolution rates (percentages of subjects 
who have symptoms at baseline and no symptoms after IMP administration) at the last 
assessment time point (the day of IMP administration) by Day 7 and the last assessment 
time point (the day after IMP administration) by Day 15, and their two-sided 95% CIs 
will be determined for each group. Fisher’s exact test will be used to compare each 
OPC-131461 dose group and the placebo group. 
For changes in jugular venous distension, hepatomegaly, and cardiothoracic ratio from 
baseline, an analysis of covariance will be performed using treatment group as a fixed 
effect and baseline value as a covariate, and the differences in the least squares means 
between each OPC-131461 dose group and the placebo group at the last assessment time 
point (the day of IMP administration) by Day 7 and the last assessment time point (the 
day after IMP administration) by Day 15, and the two-sided 95% CIs will be determined. 
For the time to resolution of each congestive finding, a Kaplan-Meier plot will be 
prepared for each treatment group in subjects with symptoms at baseline to estimate the 
median and two-sided 95% CI. 
For the NYHA Functional Classification,1 the percentages of subjects who show 
improvement by at least 1 class from baseline at the last assessment time point (the day of 
IMP administration) by Day 7 and the last assessment time point (the day after IMP 

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administration) by Day 15 among subjects classified as at least Class II, and their two-
sided 95% CIs will be determined for each group. Fisher’s exact test will be used to 
compare each OPC-131461 dose group and the placebo group. 
9.4.1.4 
Control of Experiment-wise Type 1 Error 
Control of experiment-wise type 1 error will not be performed. 
9.4.1.5 
Other Efficacy Endpoint Analysis 
Not applicable. 
9.4.2 
Safety Analysis 
The following analyses will be performed by treatment group (and by dose and overall 
for the OPC-131461 groups) on the safety analysis set. 
9.4.2.1 
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) 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  
Treatment-emergent AEs related to the IMP will be summarized similarly. Treatment-
emergent AEs by time of first onset will also be summarized. 
9.4.2.2 
Clinical Laboratory Data 
Clinical laboratory values measured at the central laboratory will be used. For clinical 
laboratory tests other than the qualitative urinalysis, the descriptive statistics of the actual 
values and changes from baseline at each time point and at the last assessment time point 
(the day after IMP administration; the same applies, hereinafter) will be calculated. A 
shift table of parameters for the qualitative urinalysis from baseline at each time point and 
the final time point of the assessment will be prepared. Parameters other than those for 
the qualitative urinalysis will be categorized based on the reference range into “within 
normal,” “below the lower limit of normal,” and “above the upper limit of normal,” and a 
shift table from baseline at each time point and the final time point of the assessment will 
be prepared. 

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9.4.2.3 
Physical Examination and Vital Signs Data 
For vital signs, descriptive statistics of the actual values and changes from baseline at 
each time point and the last assessment time point will be calculated. 
For subjects with a baseline systolic blood pressure of at least 90 mmHg, the number and 
percentage of subjects who have an actual value of “< 90 mmHg” at least once in the 
period from the time after IMP administration to the last assessment time point will be 
calculated. Similarly, the abovementioned numbers and percentages of subjects will be 
calculated at baseline and each time point after IMP administration. 
9.4.2.4 
Electrocardiogram Data 
For 12-lead ECG parameters, descriptive statistics of the actual values and changes from 
baseline at each time point and at the final assessment time point will be calculated. 
For QTc interval (QTcF), respective numbers and percentages of subjects who showed an 
actual value of “> 450 ms,” “> 480 ms,” and “> 500 ms” at least once in the period from 
the time after IMP administration to the last assessment time point will be calculated. In 
addition, respective numbers and percentages of subjects who showed a change from 
baseline of “> 30 ms” and “> 60 ms” at least once in the period from the time after IMP 
administration to the last assessment time point will be calculated. Similarly, the 
abovementioned numbers and percentages of subjects will be calculated at baseline and 
each time point after IMP administration. 
A shift table showing normal/abnormal judgment from baseline at each time point and 
the final time point of the assessment will be prepared. 
9.4.2.5 
Other Safety Data 
Not applicable. 
9.4.3 
Other Analyses 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics 
The frequency distribution or descriptive statistics of subject demographics will be 
calculated by treatment group (and by dose and overall for the OPC-131461 groups) in 
the full analysis set and safety analysis set. 
9.4.3.2 
Pharmacokinetic Analysis 
The following analyses will be performed in the PK analysis set. 
1) Endpoints 
a) Plasma concentrations of OPC-131461, M35101, and M35103 (Day 1 to 
Day 16) 

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b) Plasma pharmacokinetic parameters for OPC-131461, M35101, and M35103 
• Day 1 
Cmax, AUC24h, tmax, tlast, Cmax/D, and AUC24h/D 
• Day 7 
Cmax, AUC24h, tmax, tlast, Cmax/D, and AUC24h/D 
• Day 14 
Cmax, AUC24h, tmax, t1/2,z, CL/F#1, CL/F/BW#1, tlast, λz, Cmax/D, and 
AUC24h/D 
#1: Not calculated for metabolites 
c) Ratio of the AUC24h of M35101 or M35103 to that of OPC-131461 (Day 1, 
Day 7, and Day 14) 
d) Cumulative coefficients for OPC-131461, M35101, and M35103 (Day 7 and 
Day 14) 
• R(Cmax), R(AUC24h), and R(Ctrough) 
e) Dose proportionality of the Cmax and AUC24h of OPC-131461 (Day 1, Day 7, 
and Day 14) 
 
2) Statistical Methods 
a) Data on each of the endpoints presented in Section 9.4.3.2 1) will be 
summarized by compound, treatment group, and day of IMP administration. 
In addition, data on the endpoints shown in Section 9.4.3.2 1) a) will be 
summarized by time point of blood sampling, while data on the endpoints 
shown in Section 9.4.3.2 1) b), c), and d) will be summarized by parameter. 
The descriptive statistics to be calculated will include the number of subjects 
in the analysis set, number of subjects tabulated, arithmetic mean, standard 
deviation, coefficient of variation, and minimum, median, and maximum 
values for plasma drug concentration, and the number of subjects in the 
analysis set, number of subjects tabulated, arithmetic mean, standard 
deviation, coefficient of variation, geometric mean, and minimum, median, 
and maximum values for PK parameters. For tmax and tlast, the arithmetic 
mean, standard deviation, coefficient of variation, and geometric mean will 
not be calculated. For λz, descriptive statistics will not be calculated. 
For any parameter for which the number of tabulated subjects is half of the 
number of subjects in the analysis set or less, descriptive statistics will not be 
calculated. 
b) For the endpoints shown in Section 9.4.3.2 1) e), data will be analyzed by day 
of IMP administration using regression equation (I) to obtain an estimate of b 
and its two-sided 95% CI. 
 
In Y = a + b ∙ In X ... (I) 
 
X: Dose 
 
Y: Parameter (Cmax and AUC24h) 

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The parameter will be determined to show dose proportionality when the two-
sided 95% CI of the estimate of b includes 1. 
 
9.4.3.3 
Pharmacodynamic Analysis 
Data will be summarized by treatment group in the PD analysis set. Baseline will be the 
time point before IMP administration in the treatment period (or Day −1). 
For each endpoint, descriptive statistics of the actual values and changes from baseline at 
each time point will be calculated. 
Calculation methods for the PD effect endpoints are shown below. 
• Fluid balance: Subtract the urine volume in a time point set from the fluid intake in 
the same time point as the time point for urine accumulation. 
• Urine volume (urine excretion rate)/fluid intake/fluid balance per hour: Convert the 
urine volume/fluid intake/fluid balance in a time point set to the value per hour. 
• Cumulative urine volume/fluid intake/fluid balance and cumulative urine electrolyte 
(sodium, potassium) excretions: Sum up the values in time points for urine 
accumulation or fluid intake. If there are missing data in any of the intervals, the 
cumulative value will also be handled as missing data. 
• Daily urine volume/fluid intake/fluid balance and cumulative urine electrolyte 
(sodium, potassium) excretions: Sum up the values in time points for urine 
accumulation or fluid intake. If there are missing data in any of the intervals, the 
cumulative value will also be handled as missing data. 
• Free water clearance: Calculate using the formula below. 
Free water clearance = urine excretion rate × (serum osmolality − urine osmolality) / 
serum osmolality 
• eGFRcre: Calculate using the formula for estimation of the glomerular filtration rate 
(GFR) for Japanese8 using serum creatinine concentration, sex, and age. 
• eGFRcys: Calculate using the formula for estimation of the GFR for Japanese9 using 
serum cystatin C concentration, sex, and age. 
 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis 
No PK/PD analysis is planned. 
9.4.3.5 
Pharmacogenomic Analysis 
No pharmacogenomics analysis is planned. 
9.4.3.6 
Exploratory Endpoint Analysis 
For CA125, descriptive statistics of the actual values and changes from baseline at each 
time point will be calculated by treatment group in subjects with measurements. 

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For LVEF, descriptive statistics of the actual values and changes from baseline at each 
time point will be calculated by treatment group in subjects with measurements. The data 
will be categorized into “< 40%,” “≥ 40% to < 50%,” and “≥ 50%,” and a shift table of 
the parameter at baseline and each time point after IMP administration will be prepared 
for each treatment group. 
9.5 
Interim Analysis and Adaptive Design 
Subjects in this trial (ie, patients with CHF) may experience decreased blood flow in each 
organ, as well as decreased hepatic metabolism of OPC-131461 due to decreased hepatic 
blood flow compared to healthy adults, and therefore, different PK from that in healthy 
adults may be seen.4 In addition, this trial is the first trial to administer OPC-131461 to 
patients with CHF. For the purpose of considering the designs of subsequent trials in 
patients with CHF, an exploratory unblinded PK analysis will be performed at the 
unblinded analytical organization (the same organization as for the bioanalytical 
laboratory) before unblinding to calculate the descriptive statistics (mean, standard 
deviation, etc.) of major PK parameters (Cmax, tmax, AUC, etc.). The analysis will be 
performed at a total of 2 time points when the PK parameters can be calculated for 
approximately 6 and 25 subjects in each OPC-131461 group. The unblinded analytical 
organization will delete the individual data and report the PK analysis results (descriptive 
statistics of major PK parameters) to the sponsor. Details on the unblinded PK analysis 
are provided in a separately prepared procedure. 
No adaptive design is applicable. 
9.5.1 
Data Monitoring Committee 
Not applicable. 
 

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10 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations 
10.1.1 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, applicable ICH-GCP 
guidance, international ethical principles derived from the Declaration of Helsinki and 
Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations. Each trial site will seek approval by an IRB 
according to regional requirements, and 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, IRE, and any safety information, the 
investigator, subinvestigator, and their staff will take measures to ensure adequate care in 
protecting subject privacy. To this end, a subject ID will be used to identify each subject. 
Financial aspects, subject insurance, and the publication policy for the trial will be 
documented in the agreement between the sponsor and the trial site. 
10.1.2 
Informed Consent 
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The ICF will be approved by the 
same IRB that approves this protocol. 
Each ICF will comply with the ICH-GCP Guidelines and local regulatory requirements. 
Investigators or subinvestigators may discuss trial availability and the possibility for 
entry with a potential subject without first obtaining consent. However, informed consent 
must be obtained and documented before initiation of any procedures that are performed 
solely for the purpose of determining eligibility for this trial, including withdrawal from 
current medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.  
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator or subinvestigator (or a qualified 
designee), and it has been documented that the subject has had the opportunity to ask 
questions, the IRB-approved written ICF will be signed and dated by both the subject and 
the person obtaining consent (investigator/subinvestigator or designee), as well as by any 
other parties required by the IRB. The subject will receive a copy of the signed ICF; the 

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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 continued trial participation. Female partners 
of male subjects who become pregnant during the course of the trial may be asked to sign 
additional ICFs in order to collect additional information regarding the nonsubject partner 
and fetus. 
Separate and similar consent procedures will be followed for the optional sample 
collection for FBR. Consent must be obtained before the sample is collected. 
Participation in sample storage for FBR is optional. Refusal to participate in this aspect of 
the study will not affect participation in the main trial. 
10.1.3 
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 ID in the eCRF. 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. 
10.1.4 
Quality Control and Quality Assurance 
The sponsor will perform quality management activities for this trial in compliance with 
the ICH-GCP guidance and standard operating procedures. 
10.1.4.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the applicable ICH-GCP 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 or 

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subinvestigators and trial site personnel will undergo initial and ongoing training for this 
particular trial, and this training will be clearly documented. 
10.1.4.2 
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, site operations, delegation of authority and training, and a 
review of the eCRF with source documents, as applicable. The investigator will agree to 
cooperate and participate with audits. 
Regulatory authorities may inspect the investigator site during or after the trial. The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs. 
10.1.5 
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 or designee at the earliest possible time by telephone or via e-mail. The 
investigator/subinvestigator and sponsor (or designee) 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/subinvestigator and the sponsor (or designee), and 
reviewed by the site monitor. 
Any major protocol deviation will be recorded in the eCRF along with the start date and 
details of the deviation. 
10.1.6 
Records Management 
10.1.6.1 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, logs, and recorded data from automated instruments or 
applications. All source documents pertaining to this trial (excluding drug concentration 
measurements and materials pertaining to FBR) will be maintained by the trial site and 
made available for direct inspection by authorized persons. 
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s), by providing direct access to source data/documents by 
authorized persons as defined in the ICF. Documents related to drug concentration 

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measurement and FBR (eg, original reports, measurement data, etc) will be retained 
respectively by the bioanalytical laboratory, biorepository, and organization related to 
biospecimen research. In all cases, subject confidentiality must be maintained in 
accordance with local regulatory requirements. 
10.1.6.2 
Data Collection 
During each subject’s visit to the site, an investigator/subinvestigator or their designee 
participating in the trial will record information to document all significant observations. 
At a minimum, these notes will contain: 
• Documentation of the informed consent process, including any revised consents; 
• Documentation of the investigator/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/subinvestigator’s assessment of relationship to IMP must also be 
recorded; 
• Any changes in concomitant medications or dosages; 
• A general reference to the procedures completed, including dosing and IMP 
compliance; and, 
• The signature (or initials) and date of the investigator/subinvestigator (or designee) 
who made an entry in the medical record. 
 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. 
Any changes to the entries in medical records and other source documents will be 
initialed and dated on the day the change is made by a trial site staff member who is 
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). Unless the reason for the changes is clear, the 
investigator/subinvestigator will briefly describe the reason for the changes in the source 
documents. If an electronic data system is used, a complete audit trail of the changes 
must be maintained. 
Information from medical records and other source documents will be entered by 
investigative site personnel onto eCRFs in the sponsor’s electronic data capture (EDC) 

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system that is 21 CFR Part 11 compliant. Changes to the data will be captured by an 
automatic audit trail in the EDC system. 
Electronic data not entered on eCRF, such as data received from central laboratories or 
central ECG measurement facility, will be reconciled using key data fields by the sponsor 
or the contract research organization with the eCRF data to ensure consistency. 
10.1.6.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with the ICH-GCP guidance and as required by applicable local regulations. The trial site 
will take measures to prevent accidental or premature destruction of these documents. 
10.1.6.4 
Records Retention at the Trial Site 
The trial site will maintain all materials and records relevant to this trial for the longest of 
the following 3 periods. If the sponsor needs a longer retention, however, the trial site 
will discuss the period and method of retention with the sponsor. 
• A period of at least 2 years after the date on which approval to market the drug is 
obtained; however, if the sponsor notifies the trial site that the drug development is 
terminated or the results of the trial are not included in the NDA application form, a 
period of at least 3 years after the notification. 
• A period of at least 3 years after the trial is discontinued or completed. 
• FBR samples storage period 
 
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 to maintain adequate and accurate 
electronic or hard copy source documents of all observations and data generated during 
this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
10.1.6.5 
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 

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4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial subjects who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial subjects consent to such acknowledgement in any 
publications resulting from its conduct. 

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10.2 
Appendix 2: Clinical Laboratory Tests 
The tests described in Table 10.2-1 will be performed. 
 
Table 10.2-1 
Clinical Laboratory Assessments 
Hematology: 
Hematocrit 
Hemoglobin 
Platelets 
MCHC 
MCV 
Red blood cell count 
White blood cell count 
White blood cell differential 
(neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
 
Coagulation (plasma): 
PT-INR 
APTT 
 
Urinalysis: 
Specific gravity 
pH 
Qualitative test 
Protein 
Glucose 
Occult blood 
Ketone bodies 
Bilirubin 
Urobilinogen 
Biochemistry: 
Total protein 
Albumin 
Total bilirubin 
AST 
ALT 
ALP 
γ-GTP 
LDH 
Creatine kinase (creatine phosphokinase) (CK 
[CPK]) 
Glucose 
Total cholesterol 
Triglycerides 
Urea nitrogen 
Creatinine 
Uric acid 
Serum electrolytes (sodium, Mg, potassium, Ca, 
Cl) 
 
Additional Tests: 
Urine (or serum) pregnancy for FOCBP 
(A urine pregnancy test will be performed at 
screening and follow-up. It the result of the urine 
test is positive, a serum test will be performed.) 
 

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10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information 
Females of childbearing potential (FOCBP) are females whose menstruation has started 
and who are not documented as sterile (eg, have had a bilateral oophorectomy, or 
hysterectomy, or who have been postmenopausal for at least 12 months). Females of 
nonchildbearing potential do not meet definition of FOCBP. 
For males or their partners and FOCBP or their partners, who are sexually active, there 
must be a documented agreement that the subject and their partner will take effective 
measures (ie, 2 different approved methods of birth control) to prevent pregnancy during 
the course of the trial and for 90 days after the last dose of IMP and during the course of 
the trial and for 180 days after the last dose of IMP, respectively. Unless the subject or 
their partner is sterile (ie, females who have had a bilateral oophorectomy, have had a 
hysterectomy, or have been postmenopausal for at least 12 consecutive months; or males 
who have had a bilateral orchiectomy), and during the trial and after the last dose of IMP 
(unless 90 and 180 days have passed after the last dose of IMP in sexually active males 
and FOCBP or their partners, respectively), 2 of the following approved methods of birth 
control must be used: vasectomy, tubal ligation, IUD, birth control pill, or condom (all of 
these methods are approved in Japan). Any single method of birth control, including 
vasectomy and tubal ligation, may fail, leading to pregnancy. 
Before enrolling males and females in this clinical trial, investigators or subinvestigators 
must review the below information about trial participation as part of the ICF process. 
The topics should generally include: 
• General information 
• Informed consent form 
• Pregnancy prevention information 
• Drug interactions with hormonal contraceptives 
• Contraceptives in current use 
• Follow-up of a reported pregnancy 
 
Before trial enrollment, males and FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. Subjects must sign the ICF confirming that the above-mentioned risk factors 
and the consequences were discussed. 

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All FOCBP will undergo a urine pregnancy test (hCG) at screening. If the result of the 
urine test is positive, the investigator or subinvestigator should perform a serum test for 
confirmation. 
All FOCBP must be instructed to contact the investigator or subinvestigator immediately, 
during the trial, if they are suspected to be pregnant (eg, missed or late menstrual cycle). 
Male subjects must be instructed to contact the investigator or subinvestigator 
immediately, during the trial, if their partner is suspected to be pregnant (eg, missed or 
late menstrual cycle). 
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the serum pregnancy test is known. If pregnancy is confirmed, the IMP will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. Exceptions to trial 
discontinuation may be considered for life-threatening conditions only after consultations 
with the IRE contact (see the title page of this protocol for contact information). 
The investigator or subinvestigator must immediately notify the sponsor (within 
24 hours) of any pregnancy associated with IMP exposure during the trial and for at least 
90 and 180 days after the last dose of IMP in sexually active males or their partners and 
FOCBP or their partners, respectively, and record the event on the IRE form and forward 
it to the sponsor. The sponsor will forward the Pregnancy Surveillance Form(s) to the 
investigator or subinvestigator for monitoring the outcome of the pregnancy. 
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 the Pregnancy Surveillance 
Form(s), follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome. Infants will be followed for a minimum of 6 months 
from the date of birth. 
 

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10.4 
Appendix 4: List of Prohibited Medications 
Table 10.4-1 
Drugs, Foods, Beverages, and Supplements that May Inhibit 
CYP3A4 
Classification 
Nonproprietary Namea 
HMG-CoA reductase inhibitor 
Atorvastatin 
Therapeutic drug for dyslipidemia 
Lomitapide 
Immunosuppressant 
Cyclosporine 
Immunosuppressant 
Tacrolimus 
Antiemetic drug 
Aprepitant 
Antiemetic drug 
Fosaprepitant 
Antiemetic drug 
Fosnetupitant 
Antiarrhythmic drug 
Amiodarone 
Antiarrhythmic drug 
Verapamil 
Antihypertensive drug 
Amlodipine 
Vasodilator 
Diltiazem 
Antidiabetic drug 
Linagliptin 
Anxiolytic drug 
Alprazolam 
Anxiolytic drug 
Tofisopam 
Therapeutic drug for insomnia 
Suvorexant 
Antipsychotic drug 
Lurasidone 
Antidepressant drug 
Fluvoxamine 
Antiparkinsonian drug 
Istradefylline 
Antibiotic drug 
Azithromycin 
Antibiotic drug 
Erythromycin 
Antibiotic drug 
Clarithromycin 
Antibiotic drug 
Ciprofloxacin 
Antibiotic drug 
Josamycin 
Antibiotic drug 
Roxithromycin 
Antifungal drug 
Itraconazole 
Antifungal drug 
Clotrimazole 
Antifungal drug 
Ketoconazole 
Antifungal drug 
Fluconazole 
Antifungal drug 
Voriconazole 
Antifungal drug 
Posaconazole 
Antifungal drug 
Fosravuconazole 
Antifungal drug 
Isavuconazonium 
Antiplatelet drug 
Cilostazol 
Antiplatelet drug 
Ticagrelor 
Antituberculous drug 
Isoniazid 
Antineoplastic drug 
Asciminib 
Antineoplastic drug 
Imatinib 
Antineoplastic drug 
Entrectinib 
Antineoplastic drug 
Everolimus 
Antineoplastic drug 
Olaparib 
Antineoplastic drug 
Crizotinib 
Antineoplastic drug 
Ceritinib 
Antineoplastic drug 
Selpercatinib 
Antineoplastic drug 
Nilotinib 
Antineoplastic drug 
Pazopanib 
Antineoplastic drug 
Palbociclib 

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Table 10.4-1 
Drugs, Foods, Beverages, and Supplements that May Inhibit 
CYP3A4 
Classification 
Nonproprietary Namea 
Antineoplastic drug 
Bicalutamide 
Antineoplastic drug 
Lapatinib 
Antineoplastic drug 
Larotrectinib 
Anti-HIV drug 
Atazanavir 
Anti-HIV drug 
Darunavir 
Anti-HIV drug 
Ritonavir 
Anti-HIV drug 
Lopinavir-ritonavir 
Antiviral drug 
Nirmatrelvir-ritonavir 
Anticytomegalovirus drug 
Letermovir 
Oral contraceptive drug 
Levonorgestrel 
Oral contraceptive drug 
Levonorgestrel- 
ethinyl estradiol 
Oral contraceptive drug 
Norethisterone- 
ethinyl estradiol 
Oral contraceptive drug 
Desogestrel- 
ethinyl estradiol 
Gastric acid suppressant 
Cimetidine 
Gastric acid suppressant 
Ranitidine 
Gastric acid suppressant 
Esomeprazole 
Intestinal regulator, supplement 
Berberine 
Intestinal regulator 
Berberine-Geranium herb extract 
Therapeutic drug for overactive bladder 
Propiverine 
Therapeutic drug for hepatitis C 
Grazoprevir 
Therapeutic drug for hepatitis C 
Glecaprevir-pibrentasvir 
Corticosteroid synthesis inhibitor 
Osilodrostat 
Monoclonal antibody preparation 
Brodalumab 
Selective C5a receptor antagonist 
Avacopan 
Drug for control of hereditary 
angioedema attack 
Berotralstat 
Food and beverage 
Cranberry and products thereof (juice, etc.) 
Food and beverage 
Grapefruit and products thereof (juice, etc.) 
Food and beverage 
Seville orange and products thereof (juice, etc.) 
Food and beverage 
Blueberry and products thereof (juice, etc.) 
Supplement 
Ginkgo biloba 
Supplement 
Goldenseal (Ranunculaceae) 
Supplement, herbal remedy 
Schisandra fruit (schizandra chinensis), herbal remedy 
containing schisandra fruit 
Supplement 
Diosmin 
Supplement 
Scutellarin 
Supplement 
Piperine 
Supplement 
Peppermint essential oil 
Supplement 
Resveratrol 
aDrug combinations containing an active ingredient that falls under the category of prohibited 
concomitant medications as a single drug are prohibited for concomitant use, even if they are not 
included in this table. 
If each active ingredient contained in a drug combination that falls under the category of prohibited 
concomitant medications does not fall under the category of prohibited concomitant medications as a 
single drug, the single drug (and drug combination that contains the active ingredient and is not 
included in this table) can be used. 

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Table 10.4-2 
Drugs, Foods, Beverages, and Supplements that May Induce 
CYP3A4 
Classification 
Nonproprietary Namea 
Therapeutic drug for pulmonary 
hypertension 
Bosentan 
Antidiabetic drug 
Pioglitazone 
Central nervous system stimulant 
Modafinil 
Antiemetic drug 
Aprepitant 
Antihormone drug 
Enzalutamide 
Antihormone drug 
Mitotane 
Antiepileptic drug 
Carbamazepine 
Antiepileptic drug 
Clobazam 
Antiepileptic drug 
Topiramate 
Antiepileptic drug 
Phenytoin 
Antiepileptic drug 
Phenobarbital 
Antiepileptic drug 
Rufinamide 
Antiparkinsonian drug 
Safinamide 
Antifungal drug 
Terbinafine 
Antiplatelet drug 
Ticagrelor 
Antiplatelet drug 
Ticlopidine 
Antituberculous drug 
Rifampicin 
Antineoplastic drug 
Apalutamide 
Antineoplastic drug 
Sorafenib 
Antineoplastic drug 
Tazemetostat 
Antineoplastic drug 
Dabrafenib 
Antineoplastic drug 
Darolutamide 
Antineoplastic drug 
Vinblastine 
Antineoplastic drug 
Bexarotene 
Antineoplastic drug 
Vemurafenib 
Antineoplastic drug 
Relugolix 
Antineoplastic drug 
Lorlatinib 
Anti-HIV drug 
Etravirine 
Anti-HIV drug 
Efavirenz 
Anti-HIV drug 
Elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil 
Anti-HIV drug 
Elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide 
Anti-HIV drug 
Nevirapine 
Anti-HIV drug 
Raltegravir 
Anti-HIV drug 
Ritonavir 
Anti-HIV drug 
Rifabutin 
Anti-HIV drug 
Lopinavir 
Antiherpesvirus drug 
Amenamevir 
Therapeutic drug for rheumatoid arthritis 
Upadacitinib 
Corticosteroid 
Dexamethasone 
Corticosteroid 
Methylprednisolone 
Monoclonal antibody preparation 
Sarilumab 
Drug for liver disease 
Glycyrrhizin 
Drug for liver disease 
Glycyrrhizin-glycine-cysteine combination 
Drug for liver disease 
Glycyrrhizin-glycine-DL-methionine combination 
Food and beverage 
St. Johns Wort (Hypericum perforatum) 
Supplement 
Ginkgo biloba 
Supplement 
Echinacea (Echinacea purpurea) 

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Table 10.4-2 
Drugs, Foods, Beverages, and Supplements that May Induce 
CYP3A4 
Classification 
Nonproprietary Namea 
Supplement, herbal remedy 
Herbal remedies containing Panax ginseng, red ginseng, or 
ginseng 
Supplement 
Quercetin 
Supplement 
Glycyrrhizin 
Supplement 
Genistein 
Supplement, herbal remedy 
Herbal remedies containing Salvia miltiorrhiza 
Supplement 
Garlic 
aDrug combinations containing an active ingredient that falls under the category of prohibited 
concomitant medications as a single drug are prohibited for concomitant use, even if they are not 
included in this table. 
If each active ingredient contained in a drug combination that falls under the category of prohibited 
concomitant medications does not fall under the category of prohibited concomitant medications as a 
single drug, the single drug (and drug combination that contains the active ingredient and is not 
included in this table) can be used. 
 
Table 10.4-3 
Drugs that May Inhibit OATP1B1/3, MATE, OAT, or OCT 
Classification 
Nonproprietary Namea 
Immunosuppressant 
Cyclosporine 
Oral hematopoiesis stimulant 
Eltrombopag 
Antibiotic drug 
Sulfamethoxazole-trimethoprim 
Antibiotic drug 
Erythromycin 
Antibiotic drug 
Clarithromycin 
Antibiotic drug 
Benzylpenicillin 
Anti-HIV drug 
Atazanavir 
Anti-HIV drug 
Lopinavir-ritonavir 
Anti-HIV drug 
Ritonavir 
Anti-HIV drug 
Dolutegravir 
Antineoplastic drug 
Vandetanib 
Antiarrhythmic drug 
Quinidine 
Therapeutic drug for gout 
Probenecid 
Drug for renal function tests 
P-aminohippuric acid 
Gastric acid suppressant 
Cimetidine 
Nonsteroidal antiinflammatory drug 
Diclofenac 
aDrug combinations containing an active ingredient that falls under the category of prohibited 
concomitant medications as a single drug are prohibited for concomitant use, even if they are not 
included in this table. 
If each active ingredient contained in a drug combination that falls under the category of prohibited 
concomitant medications does not fall under the category of prohibited concomitant medications as a 
single drug, the single drug (and drug combination that contains the active ingredient and is not 
included in this table) can be used. 
 

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Table 10.4-4 
Drugs that May Induce OATP1B1/3, MATE, OAT, or OCT 
Classification 
Nonproprietary Namea 
Antituberculous drug 
Rifampicin 
Anti-HIV drug 
Efavirenz 
aDrug combinations containing an active ingredient that falls under the category of prohibited 
concomitant medications as a single drug are prohibited for concomitant use, even if they are not 
included in this table. 
 
Table 10.4-5 
Drugs that Are CYP Substrates and that, When Used with 
OPC-131461, May or May Possibly Have Reduced Actions 
Mechanism of Action 
Nonproprietary Namea 
Mineralocorticoid receptor antagonist 
Eplerenone 
Mineralocorticoid receptor antagonist 
Esaxerenone 
Mineralocorticoid receptor antagonist 
Finerenone 
aDrug combinations containing an active ingredient that falls under the category of prohibited 
concomitant medications as a single drug are prohibited for concomitant use, even if they are not 
included in this table. 
 

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10.5 
Allowability of Concomitant Use of Topical Agents among 
Prohibited Concomitant Medications 
In Section 6.5.1 in the protocol, concomitant use of “drugs, foods, beverages, and 
supplements that may inhibit or induce CYP3A4,” “drugs that may inhibit or induce 
OATP1B1/3, MATE, OAT, or OCT,” and “drugs that are CYP substrates and that, when 
used with OPC-131461, may or may possibly have reduced action” are prohibited from 
the perspective of pharmacokinetic interactions. In this section, the concept of “topical 
agents” among the above drugs in this trial is described. 
10.5.1 
Conditions for Topical Agents in This Document 
Given drug interactions between the IMP and concomitant medications, concomitant use 
of drugs that are absorbed from the gastrointestinal tract or mucosa and to a large extent, 
enter the systemic circulation to exert systemic actions should be avoided. “Topical 
agents” that can be used concomitantly are limited to those meeting the condition of little 
entry into the systemic circulation, which are defined below. 
Some agents meeting both of the conditions below may enter the systemic circulation, 
depending on the route of administration or dosage form. Such agents should be reviewed 
individually with reference to Section 10.5.2, and if any questions arise, the sponsor 
should be notified. 
[Conditions for Topical Agents that Can Be Used Concomitantly] 
Drugs that meet both of the following conditions 1) and 2) are defined as topical agents. 
1) Drugs that are used for local action 
2) Drugs that do not reach the gastrointestinal tract 
Condition 2) was determined based on the possibility of absorption from the 
gastrointestinal tract and an effect on metabolic enzymes on the gastrointestinal 
epithelia. 
 
10.5.2 
Other Remarks for Topical Agents 
Whether or not the drugs fall under the category of topical agents is determined for each 
dosage form, as follows. Dosage forms are classified according to [3] Monographs for 
Preparations, General Rules for Preparations, the Japanese Pharmacopoeia, Seventeenth 
Edition, excerpts from which are presented below (an excerpt table is presented in 
Section 10.5.3). 
• “Preparations for inhalation” and “preparations for nasal application” are not allowed 
and not deemed topical agents, because they may easily enter the systemic 
circulation. 

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• “Preparations for vaginal application” and “preparations for rectal application” are 
not allowed and not deemed topical agents, because they may easily enter the 
systemic circulation. 
• “Preparations for oro-mucosal application” excluding “preparations for gargles” are 
not allowed and not deemed topical agents, because some of them are intended to be 
used for systemic action or reach the gastrointestinal tract. 
• “Preparations for ophthalmic application” and “preparations for otic application” are 
allowed and deemed topical agents. 
• “Preparations for cutaneous application” excluding “patches” used for systemic 
action are allowed and deemed topical agents. 
 
10.5.3 
Dosage Forms that May Fall under the Category of General 
Topical Agents (Excerpted from [3] Monographs for Preparations, 
General Rules for Preparations, the Japanese Pharmacopoeia, 
Seventeenth Edition) 
Preparations are classified mainly by route of administration and application site, and 
further subdivided based on the form, function, and characteristics of the preparation. 
 
Table 10.5.3-1 
Definitions of Topical Agents among Prohibited Concomitant 
Medications 
Route of Administration and 
Application Site 
Form, Function, and Characteristics of 
Preparation 
Allowability of 
Concomitant 
Use of Topical 
Agentsa 
2. Preparations for Oro-
mucosal Application 
2.1. Tablets for Oro-
mucosal Application 
2.1.1. Troches/Lozenges 
Not allowed 
2.1.2. Sublingual 
Tablets 
Not allowed 
2.1.3. Buccal Tablets 
Not allowed 
2.1.4. Mucoadhesive 
Tablets 
Not allowed 
2.1.5. Medicated 
Chewing Gums 
Not allowed 
2.2. Liquids and 
Solutions for Oro-
mucosal Application 
2.2.1. Preparations for 
Gargles 
Allowed 
2.3. Sprays for Oro-
mucosal Application 
 
Not allowed 
2.4. Semi-solid 
Preparations for Oro-
mucosal Application 
 
Not allowed 
5. Preparations for Inhalation 
5.1. Inhalations 
5.1.1. Dry Powder 
Inhalers 
Not allowed 
5.1.2. Inhalation Liquids 
and Solutions 
Not allowed 
5.1.3. Metered-Dose 
Inhalers 
Not allowed 

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Table 10.5.3-1 
Definitions of Topical Agents among Prohibited Concomitant 
Medications 
Route of Administration and 
Application Site 
Form, Function, and Characteristics of 
Preparation 
Allowability of 
Concomitant 
Use of Topical 
Agentsa 
6. Preparations for Ophthalmic 
Application 
6.1. Ophthalmic Liquids 
and Solutions 
 
Allowed 
6.2. Ophthalmic 
Ointments 
 
Allowed 
7. Preparations for Otic 
Application 
7.1. Ear Preparations 
 
Allowed 
8. Preparations for Nasal 
Application 
8.1. Nasal Preparations 
8.1.1. Nasal Dry Powder 
Inhalers 
Not allowed 
8.1.2. Nasal Liquids and 
Solutions 
Not allowed 
9. Preparations for Rectal 
Application 
9.1. Suppositories for 
Rectal Application 
 
Not allowed 
9.2. Semi-solid 
Preparations for Rectal 
Application 
 
Not allowed 
9.3. Enemas for Rectal 
Application 
 
Not allowed 
10. Preparations for Vaginal 
Application 
10.1. Tablets for 
Vaginal Use 
 
Not allowed 
10.2. Suppositories for 
Vaginal Use 
 
Not allowed 
11. Preparations for Cutaneous 
Application 
11.1. Solid Dosage 
Forms for Cutaneous 
Application 
11.1.1. Powders for 
Cutaneous Application 
Allowed 
11.2. Liquids and 
Solutions for Cutaneous 
Application 
11.2.1. Liniments 
Allowed 
11.2.2. Lotions 
Allowed 
11.3. Sprays for 
Cutaneous Application 
11.3.1. Aerosols for 
Cutaneous Application 
Allowed 
11.3.2. Pump Sprays for 
Cutaneous Application 
Allowed 
11.4. Ointments 
 
Allowed 
11.5. Creams 
 
Allowed 
11.6. Gels 
 
Allowed 
11.7. Patches 
11.7.1. Tapes 
Not allowedb 
11.7.2. Cataplasms/Gel 
Patches 
Not allowedb 
aClassified according to the above-mentioned conditions 1 and 2. 
bConcomitant use of drugs for local action is allowed. 
 

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10.6 
Appendix 6: List of Medications Requiring Caution for 
Concomitant Use 
Table 10.6-1 
List of Medications Requiring Caution for Concomitant Use 
Classification 
Nonproprietary Name 
Remarks 
β-blocker 
Propranolol, etc. 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
β-blocker 
Metoprolol 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Calcium antagonist 
Felodipine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Coumarin 
anticoagulant drug 
Warfarin, etc. 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may reduce the effect of the 
coumarin anticoagulant. Blood coagulation time 
should be measured more frequently than usual to 
adjust the dose of the coumarin anticoagulant. 
Antiviral drug 
Maraviroc 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antiepileptic drug 
Valproic acid 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Antiepileptic drug 
Stiripentol 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Antiepileptic drug 
Zonisamide 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Salicylic acid 
derivative 
Aspirin 
OPC-131461 may enhance renal excretion and 
hepatic metabolism of a salicylic acid derivative, 
and decrease the serum concentration of the 
salicylic acid derivative. 
Benzodiazepine 
Triazolam, etc. 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Benzodiazepine 
Midazolam 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antipyretic-analgesic-
antiphlogistic drug 
Acetaminophen 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may enhance metabolism of 
acetaminophen and increase the production of its 
metabolites with hepatotoxicity. 
Antipyretic-analgesic-
antiphlogistic drug 
Buprenorphine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 

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Table 10.6-1 
List of Medications Requiring Caution for Concomitant Use 
Classification 
Nonproprietary Name 
Remarks 
Dermatological drug 
Diaphenylsulfone 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Bronchodilator 
Theophylline 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Therapeutic drug for 
bronchial 
asthma/allergic rhinitis 
Montelukast 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Cardiotonic 
drug/therapeutic drug 
for asthma 
Aminophylline 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Cardiotonic drug 
Digitalis preparation 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
reduce the effect of the drug. 
Antihypertensive drug 
Azelnidipine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antihypertensive drug 
Carvedilol 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antihypertensive drug 
Bunazosin 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Drug for blood/body 
fluids 
Clopidogrel 
The effect of OPC-131461 to induce CYP2C19 may 
increase the plasma concentration of the active 
metabolite of clopidogrel. 
Blood coagulation 
inhibitor 
Apixaban 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
reduce the effect of the drug. 
Blood coagulation 
inhibitor 
Rivaroxaban 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
reduce the effect of the drug. 
Vasodilator 
Calcium antagonist 
Nifedipine, etc. 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Vasoconstrictor 
Eletriptan 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antimalarial drug  
Mefloquine 
It has been suggested that mefloquine is 
metabolized by CYP3A. Therefore, the drug and 
OPC-131461 may affect each other. 
Antirheumatic drug 
Iguratimod 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 

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Table 10.6-1 
List of Medications Requiring Caution for Concomitant Use 
Classification 
Nonproprietary Name 
Remarks 
Antineoplastic drug 
Irinotecan 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Antineoplastic drug 
Gilteritinib 
The effect of OPC-131461 to induce CYP3A4 may 
reduce the effect of the drug. 
Antineoplastic drug 
Gefitinib 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug, and decrease the 
blood concentration of the drug or its active 
metabolite. 
Antineoplastic drug 
Tamoxifen 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug, and decrease the 
blood concentration of the drug or its active 
metabolite. 
Antineoplastic drug 
Toremifene 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug, and decrease the 
blood concentration of the drug or its active 
metabolite. 
Antineoplastic drug 
Letrozole 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug, and decrease the 
blood concentration of the drug or its active 
metabolite. 
Antifungal drug 
Caspofungin 
OPC-131461 may affect the process of caspofungin 
import and induce clearance of caspofungin, 
thereby decreasing its blood concentration. 
Antibiotic drug 
Doxycycline 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may shorten the half-life of 
the drug in blood. 
Antibiotic drug 
Chloramphenicol 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Drug for 
hyperlipidemia 
Clofibrate 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Drug for 
hyperlipidemia 
Fluvastatin 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Synthetic narcotic 
Methadone 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Sedative-hypnotic drug 
Anxiolytic drug 
Diazepam 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 

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Table 10.6-1 
List of Medications Requiring Caution for Concomitant Use 
Classification 
Nonproprietary Name 
Remarks 
Sedative-hypnotic drug 
Anxiolytic drug 
Zopiclone 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Sedative-hypnotic drug 
Anxiolytic drug 
Zolpidem 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Tricyclic antidepressant 
drug 
Imipramine, etc. 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Tetracyclic 
antidepressant drug 
Maprotiline, etc. 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Cardiovascular drug 
Selexipag 
The effect of OPC-131461 to induce a hepatic drug-
metabolizing enzyme (CYP2C8) may enhance 
metabolism of the active metabolite of selexipag. 
Cardiovascular drug 
Treprostinil 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Gastrointestinal drug 
Ondansetron 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug, and decrease the 
blood concentration of the drug or its active 
metabolite. 
Gastrointestinal drug 
Cevimeline 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug, and decrease the 
blood concentration of the drug or its active 
metabolite. 
Psychoneurotic drug 
Olanzapine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Psychoneurotic drug 
Quetiapine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Psychoneurotic drug 
Clozapine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Psychoneurotic drug 
Nortriptyline 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Psychoneurotic drug 
Haloperidol 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 

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Table 10.6-1 
List of Medications Requiring Caution for Concomitant Use 
Classification 
Nonproprietary Name 
Remarks 
Psychoneurotic drug 
Bromperidol 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Psychoneurotic drug 
Mirtazapine, etc. 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Selective reuptake 
inhibitor 
Paroxetine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Therapeutic drug for 
multiple myeloma 
Thalidomide 
OPC-131461 and the drug may enhance each 
others’ effects. 
Metabolic drug 
Eliglustat 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Metabolic drug 
Tofacitinib 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Metabolic drug 
Mycophenolate mofetil 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Metabolic drug 
Leflunomide 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism from leflunomide to its active 
metabolite. 
Central nervous system 
drug 
Donepezil 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antispasmodic drug 
Tizanidine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Natural narcotic 
Oxycodone 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Urogenital drug 
Sildenafil 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Urogenital drug 
Vardenafil 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Urogenital drug 
Vibegron 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
reduce the effect of the drug. 

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Table 10.6-1 
List of Medications Requiring Caution for Concomitant Use 
Classification 
Nonproprietary Name 
Remarks 
Urogenital drug 
Mirabegron 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
reduce the effect of the drug. 
Urogenital drug 
Therapeutic drug for 
overactive bladder 
Solifenacin succinate, 
etc. 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Therapeutic drug for 
tachyarrhythmia  
Flecainide 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes may decrease the blood 
concentration of the drug. 
Antiarrhythmic drug 
Disopyramide 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antiarrhythmic drug 
Pilsicainide 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antiarrhythmic drug 
Propafenone 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antiarrhythmic drug 
Mexiletine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Corticosteroid 
Corticosteroid 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Anthelmintic drug 
Praziquantel 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Antiprotozoal drug 
Artemether-
lumefantrine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Anti-HIV drug 
Doravirine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Anti-HIV drug 
Fosamprenavir 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Anti-HIV drug 
Rilpivirine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 

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Table 10.6-1 
List of Medications Requiring Caution for Concomitant Use 
Classification 
Nonproprietary Name 
Remarks 
Anti-HIV drug 
Rilpivirine-tenofovir 
alafenamide-
emtricitabine 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Therapeutic drug for 
hepatitis C 
Elbasvir 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Therapeutic drug for 
hepatitis C 
Sofosbuvir-velpatasvir 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Cardiovascular drug 
Tadalafil 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
Cardiovascular drug 
Macitentan 
The effect of OPC-131461 to induce hepatic drug-
metabolizing enzymes (such as CYP3A4) may 
enhance metabolism of the drug and decrease its 
blood concentration. 
 

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10.7 
Appendix 7: Protocol Amendments 
The investigator or subinvestigator will not make any changes to this protocol without the 
sponsor’s prior written consent and subsequent approval 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 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 the 
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. If necessary, 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 ICF will require similar modification. In such cases, after 
approval of the new ICF by the IRB, repeat written informed consent will be obtained 
from subjects enrolled in the trial before expecting continued participation, and before the 
amendment-specified changes in the trial are implemented. 

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10.7.1 
Protocol Amendment(s)/Administrative Change(s) 
10.7.1.1 
Protocol Amendment 1 
Amendment 1 Approval Date: 
31 Aug 2022 
 
PURPOSE: 
Changes to the time points of measurement of plasma drug concentration, serum 
electrolyte (sodium, potassium) concentrations, and urine aquaporin 2 concentration; 
correction of writing errors in the allowable time windows for examination of serum 
electrolyte (sodium, potassium) concentrations and serum osmolality; clarification of the 
contents of descriptions; correction of omissions; and, correction of other writing errors 
 
BACKGROUND: 
The time points of measurement of plasma drug concentration and serum electrolyte 
(sodium, potassium) concentrations were reviewed in consideration of feasibility. The 
time points of measurement of urine aquaporin 2 concentration were reviewed and 
changed to appropriate time points. Writing errors in the allowable time windows for 
examination of serum electrolyte (sodium, potassium) concentrations and serum 
osmolality were corrected to appropriate descriptions. With regard to handling of the 
results of blinded laboratory tests for PD evaluation, as well as use of measurements of 
serum potassium concentration obtained at the trial sites for use in considering the 
necessity of a 12-lead ECG (unscheduled examination), clear descriptions were added. 
Omissions and other writing errors were corrected. 
 
MODIFICATIONS TO THE PROTOCOL: 
Sectional Revisions: 
Changed Part 
Before Change 
After Change 
Section 1.3 
Table 1.3-1 
Schedule of 
Assessments 
Annotation 
No description 
eUrine aquaporin 2 concentration will 
be measured on Day −1 and Day 14 
(or the final IMP administration 
day). 
(The subsequent annotation symbols 
were moved down by 1 character.) 
Section 1.3 
Table 1.3-1 
Schedule of 
Assessments 
Annotation g 
12-lead ECG will be performed before 
breakfast and 2 to 4 hours postdose on 
Day 1, at a feasible postdose time on 
Day 7, and at a feasible time on other 
days. If a local or central measurement 
of serum potassium concentration is 
found to exceed 5.5 mEq/L on any day 
in the treatment period when a 12-lead 
ECG is not scheduled in the protocol, 
then an additional 12-lead ECG will be 
performed as an unscheduled 
examination. 
12-lead ECG will be performed before 
breakfast and 2 to 4 hours postdose on 
Day 1, at a feasible postdose time on 
Day 7, and at a feasible time on other 
days. If a local measurement of serum 
potassium concentration is found to 
exceed 5.5 mEq/L on any day in the 
treatment period when a 12-lead ECG is 
not scheduled in the protocol, then an 
additional 12-lead ECG will be 
performed as an unscheduled 
examination. 

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Changed Part 
Before Change 
After Change 
Section 1.3 
Table 1.3-2 
Allowable Time 
Windows for 
Postdose 
Examinations/ 
Assessments 
Plasma drug concentration 
Day 1 
2, 4, and 6 h 
postdose 
Specified time 
± 20 min 
12 h postdose 
Specified time 
± 1 h 
Day 7 and Day 14 
2, 4, and 6 h 
postdose 
Specified time 
± 20 min 
12 h postdose 
Specified time 
± 1 h 
Day 15 (EOT examination) 
36 h after Day 14 
dosing (or the final 
IMP 
administration*) 
Specified time 
± 2 h 
 
Plasma drug concentration 
Day 1 
2, 4, 6, and 8 h 
postdose 
Specified time 
± 20 min 
 
 
Day 7 and Day 14 
2, 4, 6, and 8 h 
postdose 
Specified time 
± 20 min 
 
 
Day 15 (EOT examination) 
32 h after Day 14 
dosing (or the final 
IMP 
administration*) 
Specified time 
± 90 min 
 
Section 1.3 
Table 1.3-2 
Allowable Time 
Windows for 
Postdose 
Examinations/ 
Assessments 
Serum electrolyte (sodium, potassium) 
concentrations, and serum osmolality 
Day 1 and Day 7 
4 h postdose 
Specified time 
± 10 min 
8 and 12 h postdose 
Specified time 
± 40 min 
Day 2 
8 h after Day 2 
dosing 
Specified time 
± 90 min 
Day 2 and Day 8 
24 h after Day 1 or 
Day 7 dosing 
(predose and before 
breakfast on Day 2 
or Day 8) 
Within 2 h 
predose 
 
Serum electrolyte (sodium, potassium) 
concentrations, and serum osmolality 
Day 1 and Day 7 
4-6 h postdose 
⎯ 
8-12 h postdose 
⎯ 
 
 
Day 2 
8 h after Day 2 
dosing 
Specified time 
± 1 h 
Day 2, Day 3, Day 4, Day 5, Day 6, 
Day 8, Day 10, Day 12, and Day 14 
Predose and before 
breakfast 
Within 2 h 
predose 
 
Section 1.3.2 
Screening 
• Serum electrolyte (sodium, 
potassium) concentrations 
• Serum electrolyte (sodium, potassium) 
concentrations and serum osmolality 
Section 1.3.3 
Run-in Period 
(Day −3, Day −2, 
and Day −1) 
2) After breakfast 
• Daily urine osmolality, daily urine 
electrolyte (sodium, potassium) 
concentrations, and daily urine 
aquaporin 2 concentration (on Day −3 
and Day −2) 
2) After breakfast 
• Daily urine osmolality and daily urine 
electrolyte (sodium, potassium) 
concentrations (on Day −3 and Day −2) 
Section 1.3.4 
Randomization 
and Proceeding to 
the Treatment 
Period 
2) Assignment of IMP treatment to 
subjects 
(Omitted) The investigator or 
subinvestigator will check the 
randomization number assigned in the 
IWRS. The date of randomization and 
randomization number will be recorded 
in the eCRF. 
2) Assignment of IMP treatment to 
subjects 
(Omitted) The investigator or 
subinvestigator will check the 
randomization number assigned in the 
IWRS. The date of randomization, 
randomization number, and IMP number 
will be recorded in the eCRF. 
Section 1.3.5 
Treatment Period 
(Day 1) 
3) After breakfast and 5) After IMP 
administration 
• Urine osmolality in a time point set, 
urine electrolyte (sodium, potassium) 
3) After breakfast and 5) After IMP 
administration 

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Changed Part 
Before Change 
After Change 
concentrations in a time point set, and 
urine aquaporin 2 concentration in a 
time point set 
• Urine osmolality in a time point set and 
urine electrolyte (sodium, potassium) 
concentrations in a time point set 
Section 1.3.6 
Treatment Period 
(Day 2) 
Section 1.3.7 
Treatment Period 
(Day 3 and Day 4) 
Section 1.3.8 
Treatment Period 
(Day 5) 
Section 1.3.9 
Treatment Period 
(Day 6) 
Section 1.3.11 
Treatment Period 
(Day 8) 
Section 1.3.12 
Treatment Period 
(Day 9 and 
Day 11) 
Section 1.3.13 
Treatment Period 
(Day 10) 
Section 1.3.14 
Treatment Period 
(Day 12) 
Section 1.3.15 
Treatment Period 
(Day 13) 
2) After breakfast 
• Daily urine osmolality, daily urine 
electrolyte (sodium, potassium) 
concentrations, and daily urine 
aquaporin 2 concentration 
2) After breakfast 
• Daily urine osmolality and daily urine 
electrolyte (sodium, potassium) 
concentrations 
Section 1.3.10 
Treatment Period 
(Day 7) 
2) After breakfast and 4) After IMP 
administration 
• Urine osmolality in a time point set, 
urine electrolyte (sodium, potassium) 
concentrations in a time point set, and 
urine aquaporin 2 concentration in a 
time point set 
2) After breakfast and 4) After IMP 
administration 
• Urine osmolality in a time point set and 
urine electrolyte (sodium, potassium) 
concentrations in a time point set 
Section 1.3.17 
Treatment Period 
(EOT 
Examination on 
Day 15 or the 
Withdrawal 
Examination: the 
Day after the 
Final IMP 
Administration) 
2) After breakfast 
• Daily urine osmolality, daily urine 
electrolyte (sodium, potassium) 
concentrations, and daily urine 
aquaporin 2 concentration (only for 
early completers and withdrawals) 
• Urine osmolality in a time point set, 
urine electrolyte (sodium, potassium) 
concentrations in a time point set, and 
urine aquaporin 2 concentration in a 
time point set (only for completers) 
2) After breakfast 
• Daily urine osmolality and daily urine 
electrolyte (sodium, potassium) 
concentrations (only for early completers 
and withdrawals) 
• Urine osmolality in a time point set and 
urine electrolyte (sodium, potassium) 
concentrations in a time point set (only 
for completers) 
Section 1.3.18 
Post-treatment 
Observation 
Period (Post-
treatment 
3) After breakfast 
• Daily urine osmolality, daily urine 
electrolyte (sodium, potassium) 
concentrations, and daily urine 
3) After breakfast 
• Daily urine osmolality and daily urine 
electrolyte (sodium, potassium) 
concentrations (only for early completers 
and withdrawals) 

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Changed Part 
Before Change 
After Change 
Examination on 
Day 16: 2 Days 
after the Final 
IMP 
Administration) 
aquaporin 2 concentration (only for 
early completers and withdrawals) 
• Urine osmolality in a time point set, 
urine electrolyte (sodium, potassium) 
concentrations in a time point set, and 
urine aquaporin 2 concentration in a 
time point set (only for completers) 
• Urine osmolality in a time point set and 
urine electrolyte (sodium, potassium) 
concentrations in a time point set (only 
for completers) 
Section 2 
Introduction 
Refer to the current OPC-13461 
Investigator’s Brochure (IB) for more 
detailed information. 
Refer to the current OPC-131461 
Investigator’s Brochure (IB) for more 
detailed information. 
Section 6.3 
Measures to 
Minimize/Avoid 
Bias 
(Omitted) The measurements of serum 
osmolality, plasma AVP concentration, 
urine osmolality, urine sodium 
concentration, and urine potassium 
concentration may unblind trial 
treatments, and the measurement of 
urine aquaporin 2 concentration may 
lead to an evaluation bias. Therefore, 
measurement results from laboratories 
will not be disclosed until unblinding, 
and even when the measurement results 
are disclosed for blind review by the 
sponsor, treatment assessment codes 
will not be revealed to maintain 
blindness. 
(Omitted) The measurements of serum 
osmolality, plasma AVP concentration, 
urine osmolality, urine sodium 
concentration, and urine potassium 
concentration may unblind trial 
treatments, and the measurement of urine 
aquaporin 2 concentration may lead to an 
evaluation bias. Therefore, measurement 
results from laboratories will not be 
disclosed until unblinding. 
Section 8.2.1 
Pharmacokinetic 
Blood/Plasma 
Samples 
3) Rationale for blood sampling time 
points 
(Omitted) To enable calculation of the 
necessary PK parameters after multiple 
doses, a total of 8 points including a 
point before IMP administration on 
Day 14, 3 points that are predicted to be 
around tmax of the unchanged drug (2, 
4, and 6 hours after IMP 
administration), and 4 points that are 
predicted to be in the terminal 
elimination phase of the unchanged 
drug (12, 24, 36, and 48 hours after 
IMP administration) were set, taking 
into account the above results and 
feasibility. (Omitted) Early completers 
will also undergo blood sampling at 
3 points (24, 36, and 48 hours after the 
final IMP administration) and at 1 point 
in the follow-up examination (between 
240 and 336 hours after the final IMP 
administration) for the purpose of 
confirming changes in plasma drug 
concentration after the end of IMP 
administration. 
3) Rationale for blood sampling time 
points 
(Omitted) To enable calculation of the 
necessary PK parameters after multiple 
doses, a total of 8 points including a point 
before IMP administration on Day 14, 
3 points that are predicted to be around 
tmax of the unchanged drug (2, 4, and 
6 hours after IMP administration), and 
4 points that are predicted to be in the 
terminal elimination phase of the 
unchanged drug (8, 24, 32, and 48 hours 
after IMP administration) were set, 
taking into account the above results and 
feasibility. (Omitted) Early completers 
will also undergo blood sampling at 
3 points (24, 32, and 48 hours after the 
final IMP administration) and at 1 point 
in the follow-up examination (between 
240 and 336 hours after the final IMP 
administration) for the purpose of 
confirming changes in plasma drug 
concentration after the end of IMP 
administration. 
Section 8.3.4 
Clinical 
Laboratory Tests 
for 
(Omitted) To maintain blindness, the 
results of measurements of serum 
osmolality, plasma AVP concentration, 
urine osmolality, and urine electrolyte 
(Omitted) To maintain blindness, the 
results of measurements of serum 
osmolality, plasma AVP concentration, 
urine osmolality, and urine electrolyte 

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Before Change 
After Change 
Pharmacodynamic 
Assessments 
(sodium, potassium) concentrations will 
be kept undisclosed until unblinding at 
the end of the trial. 
(sodium, potassium) concentrations will 
be kept undisclosed until unblinding at 
the end of the trial. The results of 
measurements of urine aquaporin 2 
concentration will also be kept 
undisclosed until unblinding at the end of 
the trial, because an evaluation bias may 
occur. The measurement results will be 
securely stored by the laboratory, 
reported to the investigator or 
subinvestigator after unblinding, and 
provided to the sponsor in an electronic 
file. 
Section 8.3.4 
Clinical 
Laboratory Tests 
for 
Pharmacodynamic 
Assessments 
(Omitted) If a local or central 
measurement of serum potassium 
concentration is found to exceed 
5.5 mEq/L, a 12-lead ECG will be 
performed with reference to 
Section 8.7.4. 
(Omitted) If a local measurement of 
serum potassium concentration is found 
to exceed 5.5 mEq/L, a 12-lead ECG will 
be performed with reference to 
Section 8.7.4. 
Section 8.7.1 
Clinical 
laboratory tests 
(Omitted) If a local or central 
measurement of serum potassium 
concentration is found to exceed 
5.5 mEq/L, a 12-lead ECG will be 
performed with reference to 
Section 8.7.4. 
(Omitted) If a local measurement of 
serum potassium concentration is found 
to exceed 5.5 mEq/L, a 12-lead ECG will 
be performed with reference to 
Section 8.7.4. 
Section 8.7.4 
Electrocardiogram 
Data 
(Omitted) If a local or central 
measurement of serum potassium 
concentration is found to exceed 
5.5 mEq/L on any day in the treatment 
period when a 12-lead ECG is not 
scheduled in the protocol, then an 
additional 12-lead ECG will be 
performed as an unscheduled 
examination. 
(Omitted) If a local measurement of 
serum potassium concentration is found 
to exceed 5.5 mEq/L on any day in the 
treatment period when a 12-lead ECG is 
not scheduled in the protocol, then an 
additional 12-lead ECG will be 
performed as an unscheduled 
examination. 
Section 8.8.2 
Eliciting and 
Reporting 
Adverse Events 
(Omitted) 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. 
(Omitted) 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. A 
reported AE that worsened in severity or 
seriousness should be reported as a new 
AE in the eCRF. 
 

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10.7.2 
Protocol Amendment 2 
Amendment 2 Approval Date: 
07 Mar 2023 
 
PURPOSE: 
Addition of echocardiography (LVEDV, LVESV, and LVEF); correction of the timing to 
start prohibiting concomitant use of specified medications; clarification of collection of 
data on the start time and end time of AE “vomiting;” correction of terms; correction of 
omissions; and correction of other writing errors 
 
BACKGROUND: 
Echocardiography (LVEDV, LVESV, and LVEF) were added to obtain basic information 
on heart failure and to assess the effect of OPC-131461 on left ventricular function in an 
exploratory manner. For prohibited concomitant medications that may inhibit or induce 
CYP3A4, the timing to start prohibiting concomitant use was corrected after 
consideration of the period to minimize their effects on the PK, safety, and efficacy of 
OPC-131461. For drugs that are substrates for CYP, UGT, P-gp, and OATP1B1/3, the 
timing to start prohibiting concomitant use was corrected after consideration of the period 
to minimize the effect of OPC-131461 on these drugs. Collection of data on the start time 
and end time of AE “vomiting” was clearly described, because PK assessment will be 
performed in the trial. Terms, omissions, and other writing errors were corrected. 
 
MODIFICATIONS TO THE PROTOCOL: 
Sectional Revisions: 
Changed Part 
Before Change 
After Change 
Section 1.1 
Synopsis 
Objectives and 
Endpoints 
Pharmacodynamic endpoint: 
(Omitted) 
No description 
Pharmacodynamic endpoint: 
(Omitted) 
, and free water clearance 
Section 1.1 
Synopsis 
Objectives and 
Endpoints 
Exploratory Objective: 
To explore the indicator of systemic 
congestion by comparing OPC-131461 
and placebo. 
Exploratory Objective: 
To conduct an exploratory investigation 
of OPC-131461 compared to placebo. 
Section 1.1 
Synopsis 
Objectives and 
Endpoints 
Exploratory endpoint: 
CA125 
Exploratory endpoint: 
Carbohydrate antigen 125 (CA125), 
echocardiography for left ventricular 
ejection fraction (LVEF) 
Section 1.1 
Synopsis 
Exclusion 
Criterion 17) 
Drugs, Foods, Beverages, and 
Supplements: 
Drugs, foods, beverages, and 
supplements that may inhibit or induce 
cytochrome P450 (CYP) 3A4 (see 
Table 10.4-1 and Table 10.4-2). 
(Omitted) 
 
Timing: 
14 days before IMP administration 
Drugs, Foods, Beverages, and 
Supplements: 
Drugs, foods, beverages, and 
supplements that may inhibit 
cytochrome P450 (CYP) 3A4 (see 
Table 10.4-1). (Omitted) 
 
Timing: 
4 days before IMP administration 

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Changed Part 
Before Change 
After Change 
Section 1.1 
Synopsis 
Exclusion 
Criterion 17) 
No description 
Drugs, Foods, Beverages, and 
Supplements: 
Drugs, foods, beverages, and 
supplements that may induce CYP3A4 
(See Table 10.4-2).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
 
Timing: 
8 days before IMP administration 
Section 1.1 
Synopsis 
Exclusion 
Criterion 17) 
Drugs that may inhibit or induce organic 
anion transporter polypeptide (OATP), 
multidrug and toxin extrusion (MATE), 
organic anion transporter (OAT), or 
organic cation transporter (OCT). 
Drugs that may inhibit or induce organic 
anion transporter polypeptide (OATP) 
1B1/3, multidrug and toxin extrusion 
(MATE), organic anion transporter 
(OAT), or organic cation transporter 
(OCT). 
Section 1.1 
Synopsis 
Exclusion 
Criterion 17) 
Drugs, Foods, Beverages, and 
Supplements: 
substrates for CYP, uridine diphosphate 
glucuronosyltransferase (UGT), P-
glycoprotein (P-gp), or organic anion 
transport polypeptide 1B1 (OATP1B1). 
(Omitted) 
 
Timing: 
14 days before IMP administration 
Drugs, Foods, Beverages, and 
Supplements: 
substrates for CYP, uridine diphosphate 
glucuronosyltransferase (UGT), P-
glycoprotein (P-gp), or organic anion 
transport polypeptide 1B1/3 
(OATP1B1/3). (Omitted) 
 
Timing: 
4 days before IMP administration 
Section 1.1 
Synopsis 
Investigational 
Medicinal 
Product(s), Dose, 
Dosage Regimen, 
Treatment 
Duration, 
Formulation, and 
Mode of 
Administration 
• Treatment duration: 14 days (If all 
congestive findings have been resolved 
and the investigator or subinvestigator 
judges that further improvement of 
volume overload is not necessary, 
however, treatment will be terminated 
before completing 14 days of treatment.) 
• Treatment duration: 14 days (If all 
congestive findings [lower limb edema, 
pulmonary congestion, jugular venous 
distension, hepatomegaly, pulmonary 
rales, and cardiac third sound] have been 
resolved and the investigator or 
subinvestigator judges that further 
improvement of volume overload is not 
necessary, however, treatment will be 
terminated before completing 14 days of 
treatment.) 
Section 1.1 
Synopsis 
Trial Assessments 
Exploratory endpoint: 
Blood collection for assessment of 
CA125 
Exploratory endpoint: 
Blood sampling for assessment of 
CA125 and echocardiography (LVEF) 
Section 1.3 
Table 1.3-1 
Schedule of 
Assessments 
No description 
Echocardiographyl 
Run-in Period 
♦ 
Once in the run-in period 
Day 15 and Day 16 
♦ 
Once by 2 days after the final IMP 
administration 
Section 1.3 
Table 1.3-1 
Schedule of 
Assessments 
Annotation a 
Subject enrollment and randomization: 
The interactive web response system 
(IWRS) will be used to enroll subjects at 
screening and to randomize them on 
Day 1. 
Subject enrollment and randomization: 
The interactive web response system 
(IWRS) will be used to enroll subjects at 
the time of informed consent and to 
randomize them on Day 1. 

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Section 1.3 
Table 1.3-1 
Schedule of 
Assessments 
Annotation g 
Annotation g 12-lead ECG will be 
performed before breakfast and 2 to 
4 hours postdose on Day 1, at a feasible 
postdose time on Day 7, and at a feasible 
time on other days. If a local 
measurement of serum potassium 
concentration is found to exceed 
5.5 mEq/L on any day in the treatment 
period when a 12-lead ECG is not 
scheduled in the protocol, then an 
additional 12-lead ECG will be 
performed as an unscheduled 
examination. 
Annotation k 12-lead ECG will be 
performed at a predose time and 2 to 
4 hours postdose on Day 1, at a feasible 
postdose time on Day 7, and at a feasible 
time on other days. If a local 
measurement of serum potassium 
concentration is found to exceed 
5.5 mEq/L on any day in the treatment 
period when a 12-lead ECG is not 
scheduled in the protocol, then an 
additional 12-lead ECG will be 
performed as an unscheduled 
examination. 
Section 1.3 
Table 1.3-1 
Schedule of 
Assessments 
Annotation 
No description 
Echocardiography 
Annotation h Echocardiography for left 
ventricular end-diastolic volume 
(LVEDV), left ventricular end-systolic 
volume (LVESV), and LVEF will be 
performed using the disc method 
(modified Simpson method). 
(The subsequent annotation symbols 
were moved down by 1 character.) 
Section 1.3 
Table 1.3-2 
Allowable Time 
Windows for 
Postdose 
Examinations/ 
Assessments 
No description 
Annotation a Any allowable window 
will not be applied to the starting time 
points of 0 hours after breakfast and 
0 hours postdose. 
Section 1.3.2 
Screening 
• Demographics 
(Omitted) 
complications, medical history [within 
the past 5 years prior to informed 
consent]), and classification of the 
disease underlying CHF 
• Demographics 
(Omitted) 
complications, classification of the 
complications, medical history [within 
the past 5 years prior to informed 
consent]), and classification of the 
disease underlying CHF 
Section 1.3.2 
Screening 
• BMI (Formula: BMI = body weight 
[kg] / height [m]2. BMI will be 
calculated based on the height and body 
weight at screening. The first decimal 
place will be rounded down.) 
• BMI (Formula: BMI = body weight 
[kg] / height [m]2. BMI will be 
calculated based on the height and body 
weight at screening. The first decimal 
place will be rounded up.) 
Section 1.3.3 
Run-in Period 
(Day −3, Day −2, 
and Day −1) 
No description 
(Omitted) 
Hospitalization information will be 
recorded in the eCRF. 
Section 1.3.3 
Run-in Period 
(Day −3, Day −2, 
and Day −1) 
3) At a feasible time on each evaluation 
day 
(Omitted) 
No description 
3) At a feasible time on each evaluation 
day 
(Omitted) 
• Echocardiography (disc method 
[modified Simpson method]) (LVEDV, 
LVESV, and LVEF) (once during the 
run-in period) 
Section 1.3.17 
3) At a feasible time 
(Omitted) 
3) At a feasible time 
(Omitted) 

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Treatment Period 
(EOT 
Examination on 
Day 15 or the 
Withdrawal 
Examination: the 
Day after the 
Final IMP 
Administration) 
No description 
• Echocardiography (disc method 
[modified Simpson method]) (LVEDV, 
LVESV, and LVEF) (once on Day 15 or 
in the period from the day after the final 
IMP administration to 2 days after the 
final IMP administration) 
Section 1.3.18 
Post-treatment 
Observation 
Period (Post-
treatment 
Examination on 
Day 16: 2 Days 
after the Final 
IMP 
Administration) 
3) At a feasible time 
(Omitted) 
No description 
3) At a feasible time 
(Omitted) 
• Echocardiography (disc method 
[modified Simpson method]) (LVEDV, 
LVESV, and LVEF) (once on Day 15 or 
in the period from the day after the final 
IMP administration to 2 days after the 
final IMP administration) 
Section 1.3.19 
Follow-up 
Examination 
(Day 24 to 
Day 28: 10 to 14 
Days after the 
Final IMP 
Administration) 
The investigator or subinvestigator will 
perform the following examinations and 
investigations between 10 and 14 days 
after the final IMP administration. 
Subjects who have been discharged will 
undergo the examinations and 
investigations on an outpatient basis. 
The investigator or subinvestigator will 
perform the following examinations and 
investigations between 10 and 14 days 
after the final IMP administration. 
Subjects who have been discharged will 
undergo the examinations and 
investigations on an outpatient basis. 
Discharge information will be recorded 
in the eCRF. 
Section 3 
Objectives and 
Endpoints 
Table 3-1 
Pharmacodynamic endpoint: 
(Omitted) 
No description 
Pharmacodynamic endpoint: 
(Omitted) 
, and free water clearance 
Section 3 
Objectives and 
Endpoints 
Table 3-1 
Exploratory Objective: 
To explore the indicator of systemic 
congestion by comparing OPC-131461 
and placebo. 
Exploratory Objective: 
To conduct an exploratory investigation 
of OPC-131461 compared to placebo. 
Section 3 
Objectives and 
Endpoints 
Table 3-1 
Exploratory endpoint: 
CA125 
Exploratory endpoint: 
CA125, echocardiography for LVEF 
Section 4.3 
Dosing Rationale 
• Treatment duration: 14 days (However, 
if all congestive findings have been 
resolved and the investigator or 
subinvestigator judges that further 
improvement of volume overload is not 
necessary, treatment will be terminated 
before completing 14 days of treatment.) 
• Treatment duration: 14 days (However, 
if all congestive findings [lower limb 
edema, pulmonary congestion, jugular 
venous distension, hepatomegaly, 
pulmonary rales, and cardiac third 
sound] have been resolved and the 
investigator or subinvestigator judges 
that further improvement of volume 
overload is not necessary, treatment will 
be terminated before completing 14 days 
of treatment.) 
Section 4.5 
(Omitted) 
Subjects who terminate treatment before 
completing 14 days of treatment because 
(Omitted) 
Subjects who terminate treatment before 
completing 14 days of treatment because 

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Definition of 
Completed 
Subjects 
all congestive findings have been 
resolved and the investigator or 
subinvestigator judges that further 
improvement of volume overload is not 
necessary, 
all congestive findings (lower limb 
edema, pulmonary congestion, jugular 
venous distension, hepatomegaly, 
pulmonary rales, and cardiac third 
sound) have been resolved and the 
investigator or subinvestigator judges 
that further improvement of volume 
overload is not necessary, 
Section 5.2.2 
Exclusion 
Criterion 17) 
Drugs, Foods, Beverages, and 
Supplements: 
Drugs, foods, beverages, and 
supplements that may inhibit or induce 
cytochrome P450 (CYP) 3A4 (see 
Table 10.4-1 and Table 10.4-2). 
(Omitted) 
 
Timing: 
14 days before IMP administration 
Drugs, Foods, Beverages, and 
Supplements: 
Drugs, foods, beverages, and 
supplements that may inhibit 
cytochrome P450 (CYP) 3A4 (see 
Table 10.4-1). (Omitted) 
 
Timing: 
4 days before IMP administration 
Section 5.2.2 
Exclusion 
Criterion 17) 
No description 
Drugs, Foods, Beverages, and 
Supplements: 
Drugs, foods, beverages, and 
supplements that may induce CYP3A4 
(See Table 10.4-2).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
 
Timing: 
8 days before IMP administration 
Section 5.2.2 
Exclusion 
Criterion 17) 
Drugs that may inhibit or induce organic 
anion transporter polypeptide (OATP), 
multidrug and toxin extrusion (MATE), 
organic anion transporter (OAT), or 
organic cation transporter (OCT). 
Drugs that may inhibit or induce organic 
anion transporter polypeptide (OATP) 
1B1/3, multidrug and toxin extrusion 
(MATE), organic anion transporter 
(OAT), or organic cation transporter 
(OCT). 
Section 5.2.2 
Exclusion 
Criterion 17) 
Drugs, Foods, Beverages, and 
Supplements: 
substrates for CYP, uridine diphosphate 
glucuronosyltransferase (UGT), P-
glycoprotein (P-gp), or organic anion 
transport polypeptide 1B1 (OATP1B1). 
(Omitted) 
 
Timing: 
14 days before IMP administration 
Drugs, Foods, Beverages, and 
Supplements: 
substrates for CYP, uridine diphosphate 
glucuronosyltransferase (UGT), P-
glycoprotein (P-gp), or organic anion 
transport polypeptide 1B1/3 
(OATP1B1/3). (Omitted) 
 
Timing: 
4 days before IMP administration 
Section 6.3 
Measures to 
Minimize/ 
Avoid Bias 
The measurements of serum osmolality, 
plasma AVP concentration, urine 
osmolality, urine sodium concentration, 
and urine potassium concentration may 
unblind trial treatments, (Omitted) These 
measurements will be performed at 
specified laboratories, and will not be 
performed at local laboratories. 
The measurements of serum osmolality, 
plasma AVP concentration, urine 
osmolality, urine sodium concentration, 
and urine potassium concentration may 
unblind trial treatments, (Omitted) These 
measurements during the trial will be 
performed at specified laboratories, and 
will not be performed at local 
laboratories. 

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Section 6.5.1 
Prohibited 
Medications and 
Therapies 
Table 6.5.1-1 
List of Prohibited 
Medications No. 4 
Drugs, Foods, Beverages, and 
Supplements: 
Drugs, foods, beverages, and 
supplements that may inhibit or induce 
cytochrome P450 (CYP) 3A4 (see 
Table 10.4-1 and Table 10.4-2). 
(Omitted) 
 
Timing: 
14 days before IMP administration 
Drugs, Foods, Beverages, and 
Supplements: 
Drugs, foods, beverages, and 
supplements that may inhibit 
cytochrome P450 (CYP) 3A4 (see 
Table 10.4-1). (Omitted) 
 
Timing: 
4 days before IMP administration 
Section 6.5.1 
Prohibited 
Medications and 
Therapies 
Table 6.5.1-1 
List of Prohibited 
Medications No. 5 
No description 
Drugs, Foods, Beverages, and 
Supplements: 
Drugs, foods, beverages, and 
supplements that may induce CYP3A4 
(See Table 10.4-2).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
 
Timing: 
8 days before IMP administration 
(Due to the addition of No. 5, the 
subsequent numbers were moved down 
by 1.) 
Section 6.5.1 
Prohibited 
Medications and 
Therapies 
Table 6.5.1-1 
List of Prohibited 
Medications No. 6 
Drugs that may inhibit or induce organic 
anion transporter polypeptide (OATP), 
multidrug and toxin extrusion (MATE), 
organic anion transporter (OAT), or 
organic cation transporter (OCT). 
Drugs that may inhibit or induce organic 
anion transporter polypeptide (OATP) 
1B1/3, multidrug and toxin extrusion 
(MATE), organic anion transporter 
(OAT), or organic cation transporter 
(OCT). 
Section 6.5.1 
Prohibited 
Medications and 
Therapies 
Table 6.5.1-1 
List of Prohibited 
Medications No. 7 
Drugs, Foods, Beverages, and 
Supplements: 
substrates for CYP, uridine diphosphate 
glucuronosyltransferase (UGT), P-
glycoprotein (P-gp), or organic anion 
transport polypeptide 1B1 (OATP1B1). 
(Omitted) 
 
Timing: 
14 days before IMP administration 
Drugs, Foods, Beverages, and 
Supplements: 
substrates for CYP, uridine diphosphate 
glucuronosyltransferase (UGT), P-
glycoprotein (P-gp), or organic anion 
transport polypeptide 1B1/3 
(OATP1B1/3). (Omitted) 
 
Timing: 
4 days before IMP administration 
Section 6.5.1 
Prohibited 
Medications and 
Therapies 
Rationale for 
Prohibited 
Concomitant 
Medications 
No. 4 OPC-131461 is metabolized by 
CYP3A4. Therefore, these medications 
were selected because drug interactions 
would make evaluation of the PK, 
safety, and efficacy difficult. 
No. 5 Whether or not OPC-131461 has 
the potential to serve as a substrate of 
OATP, MATE, OAT, and OCT 
(Omitted) 
No. 6 These drugs were selected because 
OPC-131461 may induce the expression 
or inhibit the actions of the metabolic 
enzymes/transporters (Omitted) 
No. 4 and No. 5  OPC-131461 is 
metabolized by CYP3A4. Therefore, 
these medications were selected because 
drug interactions would make evaluation 
of the PK, safety, and efficacy difficult. 
No. 6 Whether or not OPC-131461 has 
the potential to serve as a substrate of 
OATP1B1/3, MATE, OAT, and OCT 
(Omitted) 
No. 7 These drugs were selected because 
OPC-131461 may induce the expression 
or inhibit the activity of the metabolic 
enzymes/transporters (Omitted) 

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Section 6.5.3 
Restricted 
Medications and 
Therapies 
Table 6.5.3-1 
5) Nonsteroidal antiinflammatory drugs 
(excluding those used, as needed for 
local action.) 
5) Nonsteroidal antiinflammatory drugs 
(excluding those used, as needed for 
local action; For drugs used for local 
action, refer to those permitted for 
concomitant use in Table 10.5.3-1.) 
Section 8.5.2 
Echocardiography 
for LVEF 
No description 
Echocardiography (disc method 
[modified Simpson method]) will be 
performed to measure LVEDV, LVESV, 
and LVEF at the time points presented 
in the schedule of assessments 
(Table 1.3-1). Whenever possible, the 
measurements should be performed by 
the same examiner. The date of 
echocardiography and the measurements 
(to one decimal place) will be recorded 
in the source documents and eCRF. 
Values measured to more than one 
decimal place will be rounded to one 
decimal place. Echocardiography will 
not be required if measurement cannot 
be performed at a trial site due to 
problems securing a reservation for the 
use of measuring equipment or 
availability of measurement with the 
disc method (modified Simpson 
method). 
Section 8.8.2 
Eliciting and 
Reporting 
Adverse Events 
Note: For AEs occurring during 
hospitalization, time will also be 
recorded if possible. If the exact time of 
onset is unknown (cannot be identified 
in minutes), time in terms of hours will 
be identified. 
Note: For AEs occurring during 
hospitalization, time will also be 
recorded if possible. If the time of 
onset/resolution is unknown (cannot be 
identified in minutes), time in terms of 
hours will be identified. Particular 
attention should be paid to determination 
of the time of onset and resolution of 
vomiting during hospitalization to 
provide a basis for considering the 
extent of IMP absorption. 
Section 9.4.2.3 
Physical 
Examination and 
Vital Signs Data 
(Omitted) 
For subjects with a baseline systolic 
blood pressure of less than 90 mmHg, 
the number and percentage of subjects 
who have an actual value of 
“< 90 mmHg” at least once in the period 
from the time after IMP administration 
to the last assessment time point will be 
calculated. 
(Omitted) 
For subjects with a baseline systolic 
blood pressure of at least 90 mmHg, the 
number and percentage of subjects who 
have an actual value of “< 90 mmHg” at 
least once in the period from the time 
after IMP administration to the last 
assessment time point will be calculated. 
Section 9.4.3.6 
Echocardiography 
for LVEF 
No description 
For LVEF, descriptive statistics of the 
actual values and changes from baseline 
at each time point will be calculated by 
treatment group in subjects with 
measurements. The data will be 
categorized into “< 40%,” “≥ 40% to 
< 50%,” and “≥ 50%,” and a shift table 
of the parameter at baseline and each 

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time point after IMP administration will 
be prepared for each treatment group. 
Section 10.3 
Appendix 3: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
(Omitted) 
For males and FOCBP or their partners, 
who are sexually active, there must be a 
documented agreement that the subject 
and their partner will take effective 
measures (ie, 2 different approved 
methods of birth control) to prevent 
pregnancy during the course of the trial 
and for 90 days after the last dose of 
IMP and during the course of the trial 
and for 180 days after the last dose of 
IMP, respectively. 
(Omitted) 
For males or their partners and FOCBP 
or their partners, who are sexually 
active, there must be a documented 
agreement that the subject and their 
partner will take effective measures (ie, 
2 different approved methods of birth 
control) to prevent pregnancy during the 
course of the trial and for 90 days after 
the last dose of IMP and during the 
course of the trial and for 180 days after 
the last dose of IMP, respectively. 
Section 10.3 
Appendix 3: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
(Omitted) 
The investigator or subinvestigator must 
immediately notify the sponsor (within 
24 hours) of any pregnancy associated 
with IMP exposure during the trial and 
for at least 90 and 180 days after the last 
dose of the IMP in sexually active males 
and FOCBP or their partners, 
respectively, and record the event on the 
IRE form and forward it to the sponsor. 
(Omitted) 
The investigator or subinvestigator must 
immediately notify the sponsor (within 
24 hours) of any pregnancy associated 
with IMP exposure during the trial and 
for at least 90 and 180 days after the last 
dose of the IMP in sexually active males 
or their partners and FOCBP or their 
partners, respectively, and record the 
event on the IRE form and forward it to 
the sponsor. 
Section 10.4 
Appendix 4: List 
of Prohibited 
Medications 
Table 10.4-1 
No description 
Classification: 
Anti-SARS-CoV-2 drug 
Nonproprietary Name: 
Ensitrelvir 
 
Classification: 
Antiviral drug 
Nonproprietary Name: 
Nirmatrelvir-ritonavir 
Section 10.4 
Appendix 4: List 
of Prohibited 
Medications 
Table 10.4-1 
Food and beverage Cranberry juice 
Food and beverage Grapefruit juice 
Food and beverage Seville orange 
Food and beverage Blueberry juice 
Food and beverage Cranberry and 
products thereof (juice, etc.) 
Food and beverage Grapefruit and 
products thereof (juice, etc.) 
Food and beverage Seville orange and 
products thereof (juice, etc.) 
Food and beverage Blueberry and 
products thereof (juice, etc.) 
Section 10.4 
Appendix 4: List 
of Prohibited 
Medications 
Table 10.4-3 
Table 10.4-4 
Table 10.4-5 
Table 10.4-3 Table title 
Drugs that May Inhibit OATP, MATE, 
OAT, or OCT 
Table 10.4-4 Table title 
Drugs that May Induce OATP, MATE, 
OAT, or OCT 
Table 10.4-5 Table title 
Drugs that Are Substrates for CYP, 
UGT, P-gp, or OATP1B1 (Omitted) 
Table 10.4-3 Table title 
Drugs that May Inhibit OATP1B1/3, 
MATE, OAT, or OCT 
Table 10.4-4 Table title 
Drugs that May Induce OATP1B1/3, 
MATE, OAT, or OCT 
Table 10.4-5 Table title 
Drugs that Are Substrates for CYP, 
UGT, P-gp, or OATP1B1/3 (Omitted) 
Section 10.5 
Appendix 5: 
Allowability of 
(Omitted) “drugs that may inhibit or 
induce OATP, MATE, OAT, and OCT,” 
(Omitted) “drugs that may inhibit or 
induce OATP1B1/3, MATE, OAT, and 
OCT,” and “drugs that are substrates for 

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Concomitant Use 
of Topical Agents 
among Prohibited 
Concomitant 
Medications 
and “drugs that are substrates for CYP, 
UGT, P-gp, and OATP1B1 (Omitted) 
CYP, UGT, P-gp, and OATP1B1/3 
(Omitted) 
 

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10.7.3 
Protocol Amendment 3 
Amendment 3 Approval Date: 
15 Jun 2023 
 
PURPOSE: 
Change of inclusion criteria; deletion of exclusion criteria; review of conditions for early 
completion; change of the timing to prohibit concomitant use of specified medications; 
addition of prohibited concomitant medications; and correction of writing errors 
 
BACKGROUND: 
Adverse reactions that may occur in association with OPC-131461 are assumed to 
include increased serum sodium concentration, thirst, dehydration, and hypotension. 
However, appropriate use of vasopressin receptor antagonists in heart failure patients has 
become widespread among medical institutions after the launch of SAMSCA®, which 
has a mechanism of action similar to that of OPC-131461. In addition, subjects of this 
trial are to be hospitalized and undergo appropriate control of fluid and blood pressure 
through protocol-specified observations, examinations, and evaluations. It was therefore 
judged that there would be no problem in securing subject safety, even if the upper limit 
of subject age in the inclusion criteria was increased from 85 years to 89 years. Given the 
fact that aging of heart failure patients is seen in clinical settings, the upper limit of age 
was increased. 
Because COVID-19 was reclassified as a Class V Infectious Disease in the Infectious 
Disease Act, the necessity of a PCR test specified in the exclusion criteria was reviewed. 
Resolution of all congestive findings (lower limb edema, pulmonary congestion, jugular 
venous distension, hepatomegaly, pulmonary rales, and cardiac third sound) was required 
for early completion. However, this condition for early completion was reviewed 
considering the development of these findings for reasons other than volume overload in 
heart failure. 
Regarding prohibited concomitant medications, the timing to start prohibiting 
concomitant use of ensitrelvir, which may have an inhibitory effect on CYP3A4, was 
modified after a review of the period during which the drug affects the PK, safety, and 
efficacy of OPC-131461. Some drugs were added as prohibited concomitant medications 
that may have inhibitory effects on CYP3A4. 
Writing errors were corrected. 
 
MODIFICATIONS TO THE PROTOCOL: 
Sectional Revisions: 
Changed Part 
Before Change 
After Change 
Section 1.1 
Synopsis 
Trial Population 
A total of 155 Japanese male and female 
subjects (31 subjects each in 5 groups; 
the target number of subjects who will 
begin trial treatment), who are between 
the ages of 18 and 85 years, inclusive at 
the time of informed consent 
A total of 155 Japanese male and female 
subjects (31 subjects each in 5 groups; 
the target number of subjects who will 
begin trial treatment), who are between 
the ages of 18 and 89 years, inclusive at 
the time of informed consent 

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Section 1.1 
Synopsis 
Inclusion 
Criterion 3) 
Males or females between the ages of 18 
and 85 years inclusive (at the time of 
informed consent) 
Males or females between the ages of 18 
and 89 years inclusive (at the time of 
informed consent) 
Section 1.1 
Synopsis 
Exclusion 
Criterion 13) 
Subjects with a positive polymerase 
chain reaction (PCR) test for SARS-
CoV-2 
(Removed due to deletion in Protocol 
Amendment 3) 
(Deletion of the exclusion criterion) 
Section 1.1 
Synopsis 
Exclusion 
Criterion 17) 
No description 
Drugs, Foods, Beverages, and 
Supplements: 
Ensitrelvir 
Timing: 
11 days before IMP administration 
Section 1.1 
Synopsis 
Treatment 
duration 
14 days (If all congestive findings [lower 
limb edema, pulmonary congestion, 
jugular venous distension, hepatomegaly, 
pulmonary rales, and cardiac third sound] 
have been resolved and the investigator 
or subinvestigator judges that further 
improvement of volume overload is not 
necessary, however, treatment will be 
terminated before completing 14 days of 
treatment.) 
14 days (However the treatment will be 
terminated before completing 14 days of 
treatment, if the investigator or 
subinvestigator judges that no further 
improvement of volume overload is 
necessary in a case that all congestive 
findings [lower limb edema, pulmonary 
congestion, jugular venous distension, 
hepatomegaly, pulmonary rales, or 
cardiac third sound] were resolved or in 
other cases). 
Table 1.3-1 
PCR test 
No description 
Section 1.3.2 
[Examination 
and 
Investigation 
Items] 
• PCR test (SARS-CoV-2) 
No description 
Section 1.3.16 
The investigator or subinvestigator will 
perform the following examinations and 
investigations. 
1) After breakfast 
Subjects will be instructed to urinate 
completely after breakfast and by the 
time immediately before administration, 
and measurement of urine volume and 
fluid intake will be started after complete 
urination immediately before 
administration, which will be set as the 
starting time point to evaluate the items 
shown below. Urine volume in a time 
point set, fluid intake in a time point set, 
and fluid balance in a time point set (at 
the times specified in Table 1.3-2) will 
also be evaluated. 
• Urine volume in a time point set, fluid 
intake in a time point set, and fluid 
balance in a time point set (at the times 
specified in Table 1.3-2) 
• Urine osmolality in a time point set, 
urine electrolyte (sodium, potassium) 
concentrations in a time point set, and 
The investigator or subinvestigator will 
perform the following examinations and 
investigations. 
1) Before breakfast and IMP 
administration 
• Plasma drug concentration (at the time 
specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) 
concentrations and serum osmolality (at 
the time specified in Table 1.3-2) 
• Body weight 
• Vital signs (systolic and diastolic blood 
pressures, pulse rate, and body 
temperature) 
2) After breakfast 
Subjects will be instructed to urinate 
completely after breakfast and by the 
time immediately before administration, 
and measurement of urine volume and 
fluid intake will be started after complete 
urination immediately before 
administration, which will be set as the 
starting time point to evaluate the items 
shown below. Urine volume in a time 

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urine aquaporin 2 concentration in a time 
point set 
2) IMP administration 
The investigator or subinvestigator will 
confirm that the subject has taken the 
IMP completely, and record the date and 
time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
3) Before breakfast and IMP 
administration 
• Plasma drug concentration (at the time 
specified in Table 1.3-2) 
• Serum electrolyte (sodium, potassium) 
concentrations and serum osmolality (at 
the time specified in Table 1.3-2) 
• Body weight 
• Vital signs (systolic and diastolic blood 
pressures, pulse rate, and body 
temperature) 
point set, fluid intake in a time point set, 
and fluid balance in a time point set (at 
the times specified in Table 1.3-2) will 
also be evaluated. 
• Urine volume in a time point set, fluid 
intake in a time point set, and fluid 
balance in a time point set (at the times 
specified in Table 1.3-2) 
• Urine osmolality in a time point set, 
urine electrolyte (sodium, potassium) 
concentrations in a time point set, and 
urine aquaporin 2 concentration in a time 
point set 
3) IMP administration 
The investigator or subinvestigator will 
confirm that the subject has taken the 
IMP completely, and record the date and 
time of administration and the dose in the 
source documents and eCRF. 
• Status of IMP administration 
Section 4.1 
Type/Design of 
Trial 
During the treatment period, subjects will 
orally receive the IMP once daily for 
14 days. However, if all congestive 
findings have been resolved and the 
investigator or subinvestigator judges 
that further improvement of volume 
overload is not necessary, treatment will 
be terminated before completing 14 days 
of treatment. 
During the treatment period, subjects will 
orally receive the IMP once daily for 
14 days. However, the treatment will be 
terminated before completing 14 days of 
treatment, if the investigator or 
subinvestigator judges that no further 
improvement of volume overload is 
necessary in a case that all congestive 
findings present at baseline are resolved 
or in other cases. 
Section 4.3 
Treatment 
duration 
14 days (however, if all congestive 
findings [lower limb edema, pulmonary 
congestion, jugular venous distension, 
hepatomegaly, pulmonary rales, and 
cardiac third sound] have been resolved 
and the investigator or subinvestigator 
judges that further improvement of 
volume overload is not necessary, 
treatment will be terminated before 
completing 14 days of treatment.) 
14 days (However, the treatment will be 
terminated before completing 14 days of 
treatment, if the investigator or 
subinvestigator judges that no further 
improvement of volume overload is 
necessary in a case that any of congestive 
findings [lower limb edema, pulmonary 
congestion, jugular venous distension, 
hepatomegaly, pulmonary rales, and 
cardiac third sound] were resolved or in 
other cases.) 
Section 4.3 
[Rationale] 
Treatment is to be terminated before 
completing the 14-day treatment if all 
congestive findings have been resolved 
and the investigator or subinvestigator 
judges that further improvement of 
volume overload is not necessary. 
Treatment is to be terminated before 
completing the 14-day treatment if the 
investigator or subinvestigator judges that 
no further improvement of volume 
overload is necessary in a case that all 
congestive findings present at baseline 
are resolved or in other cases. 
Section 4.5 
Definition of 
Completed 
Subjects 
Subjects who terminate treatment before 
completing 14 days of treatment because 
all congestive findings (lower limb 
edema, pulmonary congestion, jugular 
venous distension, hepatomegaly, 
pulmonary rales, and cardiac third sound) 
Subjects who terminate treatment before 
completing 14 days of treatment, because 
the investigator or subinvestigator judges 
that no further improvement of volume 
overload is necessary in a case that all 
congestive findings (lower limb edema, 

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have been resolved and the investigator 
or subinvestigator judges that further 
improvement of volume overload is not 
necessary, and who undergo the 
evaluation at the last scheduled visit 
during the treatment period are defined as 
early completers. 
pulmonary congestion, jugular venous 
distension, hepatomegaly, pulmonary 
rales, or cardiac third sound) present at 
baseline are resolved or in other cases, 
and who undergo the evaluation at the 
last scheduled visit during the treatment 
period are defined as early completers. 
Section 5 
Trial Population 
A total of 155 Japanese male and female 
subjects (31 subjects each in 5 groups; 
the target number of subjects who will 
begin trial treatment), who are between 
the ages of 18 and 85 years, inclusive at 
the time of informed consent 
A total of 155 Japanese male and female 
subjects (31 subjects each in 5 groups; 
the target number of subjects who will 
begin trial treatment), who are between 
the ages of 18 and 89 years, inclusive at 
the time of informed consent 
Section 5.2.1.1 
Inclusion 
Criterion 3) 
Males or females between the ages of 18 
and 85 years inclusive (at the time of 
informed consent) 
Males or females between the ages of 18 
and 89 years inclusive (at the time of 
informed consent) 
Section 5.2.1.1 
Rationale for 
Inclusion 
Criterion 3) 
The lower age limit is specified to select 
subjects who are legally competent to 
provide consent and the upper age limit is 
set at 85 years based on the fact that 
cardiac edema commonly affects the 
elderly and in consideration of subject 
safety. 
The lower age limit is specified to select 
subjects who are legally competent to 
provide consent and the upper age limit is 
set at 89 years based on the fact that 
cardiac edema commonly affects the 
elderly and in consideration of subject 
safety. 
Section 5.2.2 
Exclusion 
Criterion 13) 
Subjects with a positive polymerase 
chain reaction (PCR) test for SARS-
CoV-2 
(Removed due to deletion in Protocol 
Amendment 3) 
(Deletion of the exclusion criterion) 
Section 5.2.2 
Exclusion 
Criterion 17) 
No description 
Drugs, Foods, Beverages, and 
Supplements: 
Ensitrelvir 
Timing: 
11 days before IMP administration 
Table 6.5.1-1 
No. 8 
No description 
Drugs, Foods, Beverages, and 
Supplements: 
Ensitrelvir 
Timing: 
11 days before IMP administration 
(Due to addition of the drug, the 
subsequent numbers were moved down 
by 1.) 
Section 6.5.1 
Rationale for 
Prohibited 
Concomitant 
Medications 
No. 8 
No description 
Ensitrelvir was selected because it is a 
potent CYP3A4 inhibitor and has a long 
half-life. 
(Due to addition of the rationale, the 
subsequent rationale numbers were 
moved down by 1.) 
Section 7.3.2 
As per the protocol, subjects who 
terminate treatment before completing 
the 14 days of the treatment period 
because their congestive findings have 
been resolved will undergo the 
EOT/withdrawal examination, post-
treatment examination, and follow-up 
examination at the specified timing, 
As per the protocol, subjects who 
terminate treatment before completing 
the 14 days of the treatment period 
because the investigator or 
subinvestigator judges that no further 
improvement of volume overload is 
necessary in a case that all congestive 
findings (lower limb edema, pulmonary 
congestion, jugular venous distension, 

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following the final IMP administration of 
each early completer. 
hepatomegaly, pulmonary rales, or 
cardiac third sound) present at baseline 
are resolved or in other cases will 
undergo the EOT/withdrawal 
examination, post-treatment examination, 
and follow-up examination at the 
specified timing following the final IMP 
administration of each early completer. 
Section 8.7.6 
8.7.6.1 PCR Test 
A PCR test (SARS-CoV-2) at screening 
will be performed according to the 
procedure specified by the trial site. The 
presence/absence of test, the date of test, 
and results of the test will be recorded in 
the source documents and eCRF. 
Not applicable. 
Section 10.4 
Appendix 4: 
List of 
Prohibited 
Medications 
Table 10.4-1 
No description 
Classification: 
Antiemetic drug 
Nonproprietary Name: 
Fosnetupitant 
 
Classification: 
Antifungal drug 
Nonproprietary Name: 
Fosravuconazole, isavuconazonium 
Section 10.4 
Appendix 4: 
List of 
Prohibited 
Medications 
Table 10.4-1 
Classification: 
Anti-SARS-CoV-2 drug 
Nonproprietary Name: 
Ensitrelvir 
No description 
 

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10.7.4 
Protocol Amendment 4 
Amendment 4 Approval Date: 
27 Dec 2023 
 
PURPOSE: 
Change of trial period; change of exclusion criteria; change of prohibited and restricted 
concomitant medications; correction of writing errors; clarifications of descriptions; and 
adjustments of descriptions 
 
BACKGROUND: 
Regarding the change of exclusion criteria (addition of “subjects who have undergone 
small intestine resection”), subjects who have undergone gastrectomy were to be 
excluded from the trial in the prior exclusion criteria because it may affect the absorption 
of OPC-131461, thereby affecting the evaluation of efficacy and safety. As surgical small 
intestine resection may also affect the absorption of OPC-131461, thereby affecting the 
evaluation of efficacy and safety, subjects with a history of that procedure were added to 
the protocol. 
With regard to prohibited concomitant medications, the effects of single and multiple 
coadministration of OPC-131461 20 mg and midazolam 5 mg (a sensitive CYP3A4 
substrate) on the AUC of midazolam were investigated in healthy adults in a clinical 
pharmacological trial in the United States (351-201-00007). The results of this trial 
suggested that OPC-131461 was classified as a weak CYP3A4 inducer and had no 
clinically significant effect to inhibit CYP3A4. It was therefore considered unnecessary 
to prohibit concomitant use of CYP3A4 substrates in the trial, and corrections were made 
to deem midazolam as a medication requiring caution for concomitant use. As for 
substrates of P-gp and UGT, corrections were made to exclude them from prohibited 
concomitant medications and medications requiring caution for concomitant use, because 
it is known that the effect to induce P-gp and UGT is generally weaker than that to induce 
CYP3A4. However, CYP3A4 substrates with diuretic effects were continued to be 
designated as prohibited concomitant medications, because they may affect the 
evaluation of the effect of OPC-131461. As for P-gp substrates with diuretic effects, 
OPC-131461 is not expected to have a clinically significant effect on the PK of these 
substances, because it is known that the effect to induce P-gp is generally weaker than 
that to induce CYP3A4. Thus it was considered unnecessary to prohibit their concomitant 
use. However, in order to suppress their diuretic effects and effects on fluid electrolyte 
concentrations to a certain level, corrections were made to designate them as restricted 
concomitant medications. As for OATP1B1/3 substrates, corrections were made to 
exclude them from prohibited concomitant medications and medications requiring 
caution for concomitant use, because in vitro study results suggested that they had a low 
risk of drug interactions due to OPC-131461’s inhibition of OATP1B1/3. Elvitegravir-
cobicistat-emtricitabine-tenofovir alafenamide was newly included as a prohibited 
concomitant medication because similar drugs are designated as CYP3A4 inhibitors and 
prohibited for concomitant use. With regard to prohibited concomitant medications, the 
relevant exclusion criteria were also amended. 

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Corrections of writing errors, clarifications of descriptions, and adjustments of 
descriptions were made. 
 
MODIFICATIONS TO THE PROTOCOL: 
Sectional Revisions: 
Changed Part 
Before Change 
After Change 
Section 1.1 
Inclusion 
Criterion 
(Screening 
Period) 
1) 
Subjects with CHF with lower limb 
edema, pulmonary congestion, or jugular 
venous distension due to volume 
overload. 
Subjects with CHF with any of lower 
limb edema, pulmonary congestion, or 
jugular venous distension due to volume 
overload. 
Section 1.1 
Exclusion 
Criterion 8) 
Subjects who have undergone surgical 
gastrectomy 
Subjects who have undergone surgical 
gastrectomy or small intestine resection 
Section 1.1 
Exclusion 
Criterion 17) 
Drugs that may inhibit or induce organic 
anion transporter polypeptide (OATP) 
1B1/3, multidrug and toxin extrusion 
(MATE), organic anion transporter 
(OAT), and organic cation transporter 
(OCT) (See Table 10.4-3 and 
Table 10.4-4).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
Drugs that may inhibit or induce 
OATP1B1/3, MATE, OAT, or OCT (See 
Table 10.4-3 and Table 10.4-4).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
Section 1.1 
Exclusion 
Criterion 17) 
Drugs that are substrates for CYP, 
uridine diphosphate 
glucuronosyltransferase (UGT), P-
glycoprotein (P-gp), or OATP1B1/3 and 
that, when used with OPC-131461, may 
or may possibly have reduced actions or 
cause serious adverse reactions (see 
Table 10.4-5). 
However, this does not include topical 
agents that are allowed in Section 10.5. 
Drugs that are CYP substrates and that, 
when used with OPC-131461, may or 
may possibly have reduced actions (See 
Table 10.4-5). 
However, this does not include topical 
agents that are allowed in Section 10.5. 
Section 1.1 
Synopsis 
Trial Duration 
Overall, the trial duration is from signing 
of the first informed consent form to the 
final subject assessment is expected to be 
approximately 15 months. 
Overall, the trial duration, from signing 
of the first informed consent form to the 
final subject assessment, is expected to 
be approximately 21 months. 
Section 1.3 
Schedule of 
Assessments 
No description 
Items that are not permitted to measure at 
hospitals during the trial period (See 
Section 6.3): Serum osmolality, plasma 
AVP concentration, urine osmolality, 
urine sodium concentration, urine 
potassium concentration, and urine 
aquaporin 2 concentration 
Section 1.3 
Schedule of 
Assessments 
c During the treatment period, serum 
sodium and potassium concentrations 
will be measured not only at the central 
laboratory but also at the trial site. 
g Serum sodium and potassium 
concentrations will be measured at the 
central laboratory during the screening 
period, post-treatment observation 
period, and follow-up period, and will be 
measured not only at the central 
laboratory but also at the trial sites during 
the treatment period. 

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Section 5.2.1.1 
Inclusion 
Criterion 
(Screening 
Period) 
1) 
Subjects with CHF with lower limb 
edema, pulmonary congestion, or jugular 
venous distension due to volume 
overload. 
Subjects with CHF with any of lower 
limb edema, pulmonary congestion, or 
jugular venous distension due to volume 
overload. 
Section 5.2.2 
Exclusion 
Criterion 8) 
Subjects who have undergone surgical 
gastrectomy 
Subjects who have undergone surgical 
gastrectomy or small intestine resection 
Section 5.2.2 
Exclusion 
Criterion 17) 
Drugs that may inhibit or induce 
OATP1B1/3, MATE, OAT, and OCT 
(See Table 10.4-3 and Table 10.4-4).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
Drugs that may inhibit or induce 
OATP1B1/3, MATE, OAT, or OCT (See 
Table 10.4-3 and Table 10.4-4).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
Section 5.2.2 
Exclusion 
Criterion 17) 
Drugs that are substrates for CYP, 
uridine diphosphate 
glucuronosyltransferase (UGT), P-
glycoprotein (P-gp), or OATP1B1/3 and 
that, when used with OPC-131461, may 
or may possibly have reduced actions or 
cause serious adverse reactions (see 
Table 10.4-5). 
However, this does not include topical 
agents that are allowed in Section 10.5. 
Drugs that are substrates for CYP and 
that, when used with OPC-131461, may 
or may possibly have reduced actions 
(See Table 10.4-5). 
However, this does not include topical 
agents that are allowed in Section 10.5. 
Section 6.5 
Concomitant 
Medications and 
Therapies 
(Omitted) 
For concomitant therapies, the name of 
therapy, purpose, and start and end dates 
of treatment will be recorded in the 
eCRF. 
(Omitted) 
For concomitant therapies (including salt 
restriction), the name of therapy, purpose, 
and start and end dates of treatment will 
be recorded in the eCRF. 
Section 6.5.1 
Prohibited 
Medications and 
Therapies 
Table 6.5.1-1 
Drugs that may inhibit or induce organic 
anion transporter polypeptide (OATP) 
1B1/3, multidrug and toxin extrusion 
(MATE), organic anion transporter 
(OAT), and organic cation transporter 
(OCT) (See Table 10.4-3 and 
Table 10.4-4).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
Drugs that may inhibit or induce organic 
anion transporter polypeptide (OATP) 
1B1/3, multidrug and toxin extrusion 
(MATE), organic anion transporter 
(OAT), or organic cation transporter 
(OCT) (See Table 10.4-3 and 
Table 10.4-4).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
Section 6.5.1 
Prohibited 
Medications and 
Therapies 
Table 6.5.1-1 
Drugs that are substrates for CYP, UGT, 
P-gp, or OATP1B1/3 and that, when used 
with OPC-131461, may or may possibly 
have reduced actions or cause serious 
adverse reactions (see Table 10.4-5). 
However, this does not include topical 
agents that are allowed in Section 10.5. 
Drugs that are CYP substrates and that, 
when used with OPC-131461, may or 
may possibly have reduced actions (See 
Table 10.4-5).  
However, this does not include topical 
agents that are allowed in Section 10.5. 
Section 6.5.1 
Prohibited 
Medications and 
Therapies 
No. 7 These drugs were selected because 
OPC-131461 may induce the expression 
or inhibit the activity of the metabolic 
enzymes/transporters, or because the 
possibility of such induction cannot be 
ruled out. 
No. 7 These drugs were selected because 
OPC-131461 may induce the expression 
of the metabolic enzymes, or because the 
possibility of such induction cannot be 
ruled out. 
Section 6.5.2 
Medications 
Requiring 
OPC-131461 may induce CYP3A4, and 
may also have the potential to induce 
CYPs other than CYP3A4, UGT, and 
OPC-131461 may induce CYP3A4, and 
may also have the potential to induce 
CYPs other than CYP3A4. In addition, as 

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Caution for 
Concomitant 
Use 
P-gp. In addition, as its effect (inhibitory 
effect) on the transport activity of 
substrates of OATP1B1, OATP1B3, 
MATE1, MATE2-K, OAT1, OAT3, 
OCT2, and bile salt export pump (BSEP) 
has not been investigated, the possibility 
of drug interactions cannot be ruled out. 
Therefore, careful attention should be 
paid to the concomitant use of the 
medications listed in Table 10.6-1 
between the start of IMP administration 
and the end of post-treatment 
examination because such use may cause 
interactions. 
its effect (inhibitory effect) on the 
transport activity of substrates of 
MATE1, MATE2-K, OAT1, OAT3, 
OCT2, and bile salt export pump (BSEP) 
has not been investigated, the possibility 
of drug interactions cannot be ruled out. 
Therefore, careful attention should be 
paid to the concomitant use of the 
medications listed in Table 10.6-1 
between the start of IMP administration 
and the end of post-treatment 
examination because such use may cause 
interactions. 
Section 6.5.3 
Restricted 
Medications and 
Therapies 
Table 6.5.3-1 
Diuretics other than vasopressin receptor 
antagonists (excluding eplerenone, 
esaxerenone, and finerenone) and SGLT2 
inhibitors (excluding canagliflozin) 
Diuretics other than vasopressin receptor 
antagonists (excluding eplerenone, 
esaxerenone, and finerenone) and SGLT2 
inhibitors 
Section 6.5.3 
Restricted 
Medications and 
Therapies 
These medications and therapies were 
selected to ensure that the diuretic effects 
of diet therapy (salt restriction) and drugs 
other than the IMP, as well as their 
effects on electrolyte concentrations in 
body fluids were suppressed to a certain 
level. Eplerenone, esaxerenone, 
finerenone, and canagliflozin are selected 
as prohibited concomitant medications 
(see Table 10.4-5), because their effects 
may be reduced when OPC-131461 is 
used concomitantly. Therefore, these 
drugs are excluded from the restricted 
concomitant medications. 
These medications and therapies were 
selected to ensure that the diuretic effects 
of diet therapy (salt restriction) and drugs 
other than the IMP, as well as their 
effects on electrolyte concentrations in 
body fluids were suppressed to a certain 
level. Eplerenone, esaxerenone, and 
finerenone are selected as prohibited 
concomitant medications (see 
Table 10.4-5), because their effects may 
be reduced when OPC-131461 is used 
concomitantly. Therefore, these drugs are 
excluded from the restricted concomitant 
medications. 
Section 9.4.3.2 
Pharmacokinetic 
Analysis 
2) Statistical 
methods 
The parameter will be determined to 
statistically show dose proportionality 
when the two-sided 95% CI of the 
estimate of b includes 1. 
The parameter will be determined to 
show dose proportionality when the two-
sided 95% CI of the estimate of b 
includes 1. 
Section 10.3 
Appendix 3: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
(Omitted) 
If a subject is suspected to be pregnant 
before she receives the IMP, the IMP 
administration must be withheld until the 
result of a pregnancy test is available. 
(Omitted) 
If a subject is suspected to be pregnant 
before she receives IMP, the IMP 
administration must be withheld until the 
result of a serum pregnancy test is 
available. 
Section 10.4 
Appendix 4: 
List of 
Prohibited 
Medications 
Table 10.4-2 
No description 
Classification: 
Anti-HIV drug 
Nonproprietary Name: 
Elvitegravir-cobicistat-emtricitabine-
tenofovir alafenamide 
Section 10.4 
Appendix 4: 
List of 
The following changes were made (deleted parts are shown with a strikethrough, 
while corrected parts are shown in bold): 
 

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Prohibited 
Medications 
Table 10.4-5 
Table 10.4-5 Drugs that Are CYP, UGT, P-gp, or OATP1B1/3 Substrates and that, 
When Used with OPC-131461, May or May Possibly Have Reduced Actions or 
Cause Serious Adverse Reactions 
Mechanism of Action 
Nonproprietary Namea 
Mineralocorticoid receptor antagonist 
Eplerenone 
Mineralocorticoid receptor antagonist 
Esaxerenone 
Mineralocorticoid receptor antagonist 
Finerenone 
SGLT2 inhibitor 
Canagliflozin 
Anthelmintic drug 
Praziquantel 
Antifungal drug 
Voriconazole 
Antiprotozoal drug 
Artemether-lumefantrine 
Antiherpesvirus drug 
Amenamevir 
Anti-HIV drug 
Atazanavir 
Anti-HIV drug 
Elvitegravir-cobicistat-emtricitabine-
tenofovir alafenamide 
Anti-HIV drug 
Elvitegravir-cobicistat-emtricitabine-
tenofovir disoproxil 
Anti-HIV drug 
Darunavir-cobicistat 
Anti-HIV drug 
Darunavir-cobicistat-emtricitabine-
tenofovir alafenamide 
Anti-HIV drug 
Tenofovir alafenamide 
Anti-HIV drug 
Doravirine 
Anti-HIV drug 
Dolutegravir-rilpivirine 
Anti-HIV drug 
Bictegravir-emtricitabine-tenofovir 
alafenamide 
Anti-HIV drug 
Fosamprenavir 
Anti-HIV drug 
Rilpivirine 
Anti-HIV drug 
Rilpivirine-tenofovir alafenamide-
emtricitabine 
Antiviral drug 
Nirmatrelvir-ritonavir 
Therapeutic drug for hepatitis C 
Elbasvir 
Therapeutic drug for hepatitis C 
Grazoprevir 
Therapeutic drug for hepatitis C 
Glecaprevir-pibrentasvir 
Therapeutic drug for hepatitis C 
Sofosbuvir 
Therapeutic drug for hepatitis C 
Sofosbuvir-velpatasvir 
Therapeutic drug for hepatitis C 
Ledipasvir-sofosbuvir 
Antiplatelet drug 
Ticagrelor 
Cardiovascular drug 
Tadalafil 
Cardiovascular drug 
Macitentan 
Antipsychotic drug 
Lurasidone 
HMG-CoA reductase inhibitor 
Atorvastatin 
Ca antagonist/HMG-CoA reductase 
inhibitor 
Amlodipine-atorvastatin 
Small intestinal cholesterol transporter 
inhibitor/HMG-CoA reductase inhibitor 
Ezetimibe-atorvastatin 
HMG-CoA reductase inhibitor 
Simvastatin 
aDrug combinations containing an active ingredient that falls under the category of 
prohibited concomitant medications as a single drug are prohibited for 
concomitant use, even if they are not included in this table. 
If each active ingredient contained in a drug combination that falls under the 
category of prohibited concomitant medications does not fall under the category 
of prohibited concomitant medications as a single drug, the single drug (and 

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drug combination that contains the active ingredient and is not included in this 
table) can be used. 
Section 10.5 
Appendix 5: 
Allowability of 
Concomitant 
Use of Topical 
Agents among 
Prohibited 
Concomitant 
Medications 
“drugs that may inhibit or induce 
OATP1B1/3, MATE, OAT, and OCT,” 
and “drugs that are substrates for CYP, 
UGT, P-gp, or OATP1B1/3 and that, 
when used with OPC-131461, may or 
may possibly have reduced actions or 
cause serious adverse reactions” 
“drugs that may inhibit or induce 
OATP1B1/3, MATE, OAT, or OCT,” 
and “drugs that are CYP substrates and 
that, when used with OPC-131461, may 
or may possibly have reduced actions” 
Section 10.6 
Appendix 6: 
List of 
Medications 
Requiring 
Caution for 
Concomitant 
Use 
Table 10.6-1 
No description 
Classification: 
Anthelmintic drug 
Nonproprietary Name: 
Praziquantel 
Classification: 
Antiprotozoal drug 
Nonproprietary Name: 
Artemether-lumefantrine 
Classification: 
Anti-HIV drug 
Nonproprietary Name: 
Doravirine 
Classification: 
Anti-HIV drug 
Nonproprietary Name: 
Fosamprenavir 
Classification: 
Anti-HIV drug 
Nonproprietary Name: 
Rilpivirine 
Classification: 
Anti-HIV drug 
Nonproprietary Name: 
Rilpivirine-tenofovir alafenamide-
emtricitabine 
Classification: 
Therapeutic drug for hepatitis C 
Nonproprietary Name: 
Elbasvir 
Classification: 
Therapeutic drug for hepatitis C 
Nonproprietary Name: 
Sofosbuvir-velpatasvir 
Classification: 
Cardiovascular drug 
Nonproprietary Name: 
Tadalafil 
Classification: 
Cardiovascular drug 
Nonproprietary Name: 
Macitentan 
Section 10.6 
Classification: 
Therapeutic drug for nephrogenic anemia 
No description 

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Appendix 6: 
List of 
Medications 
Requiring 
Caution for 
Concomitant 
Use 
Table 10.6-1 
Nonproprietary Name: 
Roxadustat 
Classification: 
Drug for hyperlipidemia 
Nonproprietary Name: 
Pitavastatin 
Classification: 
Antibiotic drug 
Nonproprietary Name: 
Rifaximin 
Classification: 
Therapeutic drug for multiple myeloma 
Nonproprietary Name: 
Thalidomide 
Classification: 
Blood coagulation inhibitor 
Nonproprietary Name: 
Dabigatran 
Classification: 
Antiviral drug 
Nonproprietary Name: 
Zidovudine 
Classification: 
Antiepileptic drug 
Nonproprietary Name: 
Lamotrigine 
Classification: 
Antidote 
Nonproprietary Name: 
Deferasirox 
Section 10.6 
Appendix 6: 
List of 
Medications 
Requiring 
Caution for 
Concomitant 
Use 
Table 10.6-1 
The following changes were made (deleted parts are shown with a strikethrough): 
 
Classification 
Nonproprietary 
Name 
Remarks 
Cardiotonic drug 
Digitalis 
preparation 
The effect of OPC-131461 to induce 
hepatic drug-metabolizing enzymes 
(such as CYP3A4) and P-gp may 
reduce the effect of the drug. 
Blood coagulation 
inhibitor 
Apixaban 
The effect of OPC-131461 to induce 
hepatic drug-metabolizing enzymes 
(such as CYP3A4) and P-gp may 
reduce the effect of the drug. 
Blood coagulation 
inhibitor 
Rivaroxaban 
The effect of OPC-131461 to induce 
hepatic drug-metabolizing enzymes 
(such as CYP3A4) and P-gp may 
reduce the effect of the drug. 
Antineoplastic 
drug 
Gilteritinib 
The effect of OPC-131461 to induce 
CYP3A4 and P-gp may reduce the 
effect of the drug. 
Urogenital drug 
Vibegron 
The effect of OPC-131461 to induce 
hepatic drug-metabolizing enzymes 
(such as CYP3A4) and P-gp may 
reduce the effect of the drug. 

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Urogenital drug 
Mirabegron 
The effect of OPC-131461 to induce 
hepatic drug-metabolizing enzymes 
(such as CYP3A4) and P-gp may 
reduce the effect of the drug. 
 
ADDITIONAL RISKS TO THE SUBJECT: 
No additional risks will be imposed on the subjects. 
 

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11 
References 
1 
Japanese Circulation Society, et al. JCS 2017/JHFS 2017 Guideline on Diagnosis and 
Treatment of Acute and Chronic Heart Failure. 2018. 
2 
Matsuzaki M, Hori M, Tohru Izumi, 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(Suppl 1):S33-S45. 
3 
Goldsmith SR, Gheorghiade M. Vasopressin Antagonism in Heart Failure. J Am Coll 
Cardiol. 2005;46(10):1785-91. 
4 
Kato R (supervising ed.), Ieiri I, Kusuhara H (eds.). Clinical Pharmacokinetics. 
Amendment 5. Nankodo. 2017. 
5 
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. 
6 
Ministry of Health, Labour and Welfare. Regarding clinical studies utilizing 
pharmacogenomics: PFSB/ELD Notification No. 0930007. 2008. 
7 
Ministry of Health, Labour and Welfare. Guidelines on genomic sampling and 
management of genomic data: PSEHB/PED Notification No. 0118-1. 2018. 
8 
Matsuo S. New development of measures against CKD (chronic kidney disease). J. 
Jpn. Soc. Dial. Ther. 2009;42(4):317-23. 
9 
Japanese Society of Nephrology (ed.). Evidence-based Clinical Practice Guide for 
CKD 2018. Tokyo Igakusha. 2018. 
 
 
 

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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 them to ensure that they are 
sufficiently informed regarding the investigational new drug (OPC-131461), 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-131461 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 
authorities 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, I do not comply with the protocol to eliminate an immediate hazard to subjects, I will 
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 Name 
 
__________________________ 
__________________________ 
Signature 
Date 
This agreement is electronically signed by the sponsor. The sponsor signature page is 
attached to this document.