Conditions: Congestive Heart Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 61
Healthy volunteers: no

Brief summary:
The dose for intravenous administration of OPC-61815 achieving tolvaptan exposure equivalent to that for oral administration of tolvaptan 15-mg tablet will be investigated by administering OPC-61815 injection 2 to 16mg or tolvaptan 15-mg oral tablet to subjects with congestive heart failure.

Detailed description:

Arms:
arm 1: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 2 mg. arm 2: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 4 mg. arm 3: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 8 mg. arm 4: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg. arm 5: Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.

Interventions: intervention 1: OPC-61815 injection 2mg intervention 2: OPC-61815 injection 4mg intervention 3: OPC-61815 injection 8mg intervention 4: OPC-61815 injection 16mg intervention 5: Tolvaptan tablet 15mg
Intervention descriptions: intervention 1: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 2 mg. intervention 2: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 4 mg. intervention 3: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 8 mg. intervention 4: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg. intervention 5: Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group Comparison 
Clinical Pharmacology Trial to Investigate the Dose of OPC-61815 Injection Equivalent  
to Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure 
 
 
 
 
NCT Number: NCT03254108 
PRT NO.: 263-102-00001 
Version Date: 19 June 2017 (Version 2.0) 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
1 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Otsuka Pharmaceutical Co., Ltd 
 
Investigational Medicinal Product 
 
OPC-61815 
 
CLINICAL PROTOCOL 
 
A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group Comparison 
Clinical Pharmacology Trial to Investigate the Dose of OPC-61815 Injection Equivalent 
to Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure 
 
Protocol No. 263-102-00001 
 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase:  
 
2 
 
Sponsor: 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd 
 
Immediately Reportable Event:  
Department of Pharmacovigilance 
 
Otsuka Pharmaceutical Co., Ltd 
 
Email: IRE_263-102-00001@otsuka.jp 
 
 
 
 
 
 
 
Issue Date: 
 
 
 
 
19 Jun 2017 
 
Version No.:  
 
 
 
2.0 
 
 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
2 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Protocol Synopsis  
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd 
Name of Investigational Medicinal Product: OPC-
61815 
Protocol No.: 263-102-00001 
Protocol Title: 
A Multicenter, Double-blind, Randomized, Active-controlled, 
Parallel-group Comparison Clinical Pharmacology Trial to 
Investigate the Dose of OPC-61815 Injection Equivalent to 
Tolvaptan 15-mg Tablet in Patients With Congestive Heart 
Failure (CHF) 
Clinical Phase/Trial 
Type: 
2 / Clinical pharmacology 
Treatment Indication:  CHF patients with volume overload despite having received 
diuretics other than vasopressin antagonists 
Objective(s):  
Primary: To investigate the dose of OPC-61815 injection 
formulation achieving exposure equivalent to that for tolvaptan 
15-mg tablet by 1-hour intravenous administration of OPC-
61815 at 2, 4, 8, or 16 mg once daily or oral administration of 
tolvaptan tablet at 15 mg once daily for 5 days in CHF patients 
with volume overload despite having received diuretics other 
than vasopressin antagonists 
Secondary: To investigate the efficacy, pharmacokinetics, 
pharmacodynamics, and safety of OPC-61815 in comparison 
with tolvaptan tablet by 1-hour intravenous administration of 
OPC-61815 at 2, 4, 8, or 16 mg once daily or oral 
administration of tolvaptan tablet at 15 mg once daily for 5 
days in CHF patients with volume overload despite having 
received diuretics other than vasopressin antagonists. 
Trial Design: 
A multicenter, randomized, double-blind, active controlled 
(with tolvaptan tablet), double-dummy, parallel group 
comparison trial 
Subject Population: 
Japanese male and female CHF patients with volume overload 
despite having received diuretics other than vasopressin 
antagonists, age 20 to 85 years, inclusive (Sample size: A total 
of 50 subjects, comprising 10 subjects in each groupNote) 
Note: Subject enrollment will be conducted to ensure that there 
are ≥10 subjects per group who complete blood sampling for 
measurement of plasma drug concentrations up until 24 hours 
postdose on Day 1. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
3 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Inclusion/Exclusion 
Criteria:  
Main criteria for inclusion: 
• 
Subjects who are currently on treatment with any of the 
following diuretics 
− 
Loop diuretics equivalent to furosemide tablet or fine 
granules at a dose of 40 mg/day or higher 
− 
Concomitant use of a loop diuretic and a thiazide 
diuretic (including thiazide analogs) at any dose 
− 
Concomitant use of a loop diuretic and an aldosterone 
antagonist or potassium-sparing diuretic agent at any 
dose 
• 
Subjects with CHF in whom lower limb edema, 
pulmonary congestion, and/or jugular venous distension 
due to volume overload is present 
• 
Male or female subjects at age 20 to 85 years, inclusive, at 
time of informed consent 
• 
Subjects who are currently hospitalized or who are able to 
be hospitalized during the trial 
• 
Subjects who are capable of taking oral tablets 
• 
Subjects who are given diuretic agents with no change in 
dose or regimen during the run-in period 
• 
Subjects with no more than 1.0 kg change in body weight 
over the 2 days (Day −2 to Day −1 of the run-in period) 
prior to investigational medicinal product (IMP) 
administration 
Main criteria for exclusion: 
• 
Subjects with acute heart failure 
• 
Subjects with mainly noncardiogenic congestive 
symptoms 
• 
Subjects who are on an ventricular assist device 
• 
Subjects who are suspected of having hypovolemia, 
hypertrophic cardiomyopathy (excluding dilated phase), 
valvular disease with significant valvular stenosis, or 
hepatic encephalopathy with difficulty in adequate fluid 
intake 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
4 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
• 
Subjects who have experienced acute myocardial 
infarction within 30 days prior to the screening 
examination 
• 
Subjects with definite diagnosis of active myocarditis or 
amyloid cardiomyopathy 
• 
Subjects with poorly controlled diabetes mellitus, anuria, 
or dysuria associated with urinary tract obstruction, 
calculus, or tumor 
• 
Subjects with a history of hypersensitivity to any of 
ingredients of OPC-61815 or tolvaptan 
• 
Subjects with a history of hypersensitivity or idiosyncratic 
reaction to benzazepine or benzazepine derivatives such as 
mozavaptan hydrochloride and benazepril hydrochloride 
• 
Subjects who are severely obese (body mass index [BMI], 
body weight [kg]/height [m]2 exceeding 35 kg/m2) 
• 
Subjects with supine systolic blood pressure of 
<90 mmHg 
• 
Subjects with any of the following laboratory test 
abnormalities: Total bilirubin, >3.0 mg/dL; serum 
creatinine, >3.0 mg/dL; serum sodium >147 mEq/L; 
serum potassium, >5.5 mEq/L 
• 
Subjects with concurrent symptoms or history of hepatic 
impairment 
• 
Subjects who are unable to sense thirst or who have 
difficulty with fluid intake 
Trial Site(s):  
Approximately 40 trial sites in Japan 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
5 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration: 
Lyophilized formulation containing 2, 4, 8, or 16 mg of OPC-
61815 or placebo in a vial and tolvaptan 15-mg tablet or 
placebo tablet. 
This trial will be conducted using a double-dummy design to 
maintain blindness. Subjects will receive a combination of 
either OPC-61815 injection and placebo tablet or placebo 
injection and tolvaptan 15-mg tablet. Once daily for 5 days 
either tolvaptan 15-mg tablet or placebo tablet will be orally 
administered, followed immediately by 1-hour intravenous 
administration of either OPC-61815 at 2, 4, 8, or 16 mg or 
placebo. 
As there will be a difference in appearance between the OPC-
61815 solution and the placebo solution at the time of 
preparation, the person responsible for IMP preparation at the 
trial site (non-blinded staff) will prepare the double-blinded 
IMP, which will then be administered by the investigator or 
subinvestigators, etc. 
Trial Assessments: 
 
Pharmacokinetics: Blood sampling for measurement of 
plasma concentrations of parent drugs and metabolites 
Pharmacodynamics: Blood sampling for serum 
concentrations of sodium and potassium, serum osmolality, 
and biomarker measurements; and urine sampling or 
cumulative urine volume collection for daily urine volume, 
daily fluid balance, daily urine sodium excretion, daily urine 
potassium excretion, urine osmolality, and daily fluid intake 
Efficacy: Body weight, congestive symptoms (lower limb 
edema, other edema, jugular venous distension, pulmonary 
congestion confirmed by chest X-ray, pulmonary rales, third 
cardiac sound, and hepatomegaly), cardiothoracic ratio, and 
NYHA classification 
Safety: Adverse event reporting, clinical laboratory tests, 
physical examination, vital signs (blood pressure, pulse rate, 
and body temperature), and 12-lead electrocardiogram 
Screening: Medical and medication history, physical 
examination, clinical laboratory tests, vital signs, body weight, 
and urine pregnancy test, etc. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
6 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Criteria for 
Evaluation: 
Primary Endpoint: 
• 
Tolvaptan exposure (maximum [peak] plasma drug 
concentration [Cmax] and area under the concentration-
time curve from time zero to 24 hours [AUC24h] on Day 
1 of the treatment period) 
Secondary Endpoint(s): 
• 
Pharmacokinetics: Plasma concentrations and 
pharmacokinetic parameters of OPC-61815, tolvaptan, 
DM-4103, and DM-4107 
• 
Pharmacodynamics: Serum concentrations of sodium and 
potassium, serum osmolality, biomarkers (plasma 
concentrations of arginine vasopressin and brain 
natriuretic peptide, plasma renin activity, and serum 
concentrations of NT-proBNP and troponin), daily urine 
volume, daily fluid intake, daily fluid balance, daily urine 
sodium excretion, daily urine potassium excretion, and 
urine osmolality 
• 
Efficacy: Body weight, congestive symptoms (lower limb 
edema, other edema, jugular venous distension, pulmonary 
congestion confirmed by chest X-ray, pulmonary rales, 
third cardiac sound, and hepatomegaly), cardiothoracic 
ratio, and NYHA classification 
• 
Safety: Adverse event reporting, clinical laboratory tests 
(including pregnancy test), physical examination, vital 
signs (blood pressure, pulse rate, and body temperature), 
and 12-lead electrocardiogram 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
7 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Statistical Methods: 
Statistical Methods for Primary Endpoint:  
For each parameter for tolvaptan exposure (Cmax and AUC24h 
on Day 1 of the treatment period), descriptive statistics will be 
calculated for each group. The descriptive statistics calculated 
will include number of subjects, arithmetic mean, standard 
deviation, coefficient of variation, geometric mean, minimum, 
median, and maximum values. For each parameter, the 
differences (each OPC-61815 group − tolvaptan 15-mg tablet 
group) in the mean value and its 95% confidence interval will 
be calculated using logarithmic transformation (natural 
logarithm). 
Rationale for Sample Size: 
The primary objective of this clinical trial is to compare 
tolvaptan exposure in order to investigate the dose of OPC-
61815 injection required to achieve exposure equivalent to 
tolvaptan 15-mg tablet for use in conducting phase 3 
confirmatory clinical trials of OPC-61815. The number of 
subjects required for this purpose was determined to be at least 
10 subjects per group (50 subjects in total) who complete 
blood sampling for measurement of plasma drug 
concentrations up until 24 hours postdose on Day 1. In 
consideration of the possibility of some subjects withdrawing 
from the trial prior to 24 hours postdose on Day 1, the 
approximate target number of subjects for the start of IMP 
administration is set at 11 subjects per group (55 subjects in 
total). 
Trial Duration: 
Planned duration of the clinical trial: Jul 2017 to May 2018 
Planned duration of trial participation for each subject: 
Maximum of 22 days (screening [4 to 7 days before start of 
IMP administration], 3 days for run-in period, 6 days for 
treatment period, and post-treatment follow-up at Day 7 to Day 
10 after the final IMP administration) 
 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
8 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Table of Contents  
Protocol Synopsis ........................................................................................... 2 
Table of Contents ........................................................................................... 8 
List of In-text Tables ................................................................................... 13 
List of In-text Figures .................................................................................. 15 
List of Appendices........................................................................................ 16 
List of Abbreviations and Definitions of Terms ....................................... 17 
1 
Introduction ........................................................................................ 19 
1.1 
Nonclinical Data ................................................................................................20 
1.2 
Clinical Data ......................................................................................................21 
1.3 
Known and Potential Risks and Benefits ..........................................................24 
2 
Trial Rationale and Objectives.......................................................... 24 
2.1 
Trial Rationale ...................................................................................................24 
2.2 
Justification for DNA storage............................................................................25 
2.3 
Dosing Rationale ...............................................................................................26 
2.4 
Trial Objectives .................................................................................................32 
3 
Trial Design ......................................................................................... 32 
3.1 
Type/Design of Trial .........................................................................................32 
3.2 
Trial Treatments ................................................................................................34 
3.2.1 
Dose and Regimen and Duration of Treatment ..............................................34 
3.2.2 
IMP Preparation ..............................................................................................35 
3.3 
Trial Population .................................................................................................35 
3.3.1 
Number of Subjects and Description of Population .......................................35 
3.3.2 
Subject Selection and Numbering ..................................................................36 
3.4 
Eligibility Criteria..............................................................................................36 
3.4.1 
Informed Consent ...........................................................................................36 
3.4.2 
Inclusion Criteria ............................................................................................37 
3.4.3 
Criteria for Enrollment in the Treatment Period (Inclusion Criteria of 
Run-in Period) ................................................................................................38 
3.4.4 
Exclusion Criteria ...........................................................................................38 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
9 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.5 
Endpoints ...........................................................................................................40 
3.5.1 
Primary Endpoint ............................................................................................40 
3.5.2 
Secondary Endpoints ......................................................................................40 
3.5.3 
Safety Endpoints .............................................................................................41 
3.5.4 
Rationale for Endpoints ..................................................................................41 
3.6 
Measures to Minimize/Avoid Bias ....................................................................42 
3.6.1 
Randomization ................................................................................................42 
3.6.2 
Blinding ..........................................................................................................42 
3.7 
Trial Procedures ................................................................................................42 
3.7.1 
Schedule of Assessments ................................................................................45 
3.7.1.1 
Screening .....................................................................................................45 
3.7.1.2 
Run-in Period (Day −3, Day −2, and Day −1) ............................................45 
3.7.1.3 
Randomization and Initiation of Treatment Period .....................................46 
3.7.1.4 
Treatment Period (Day 1)............................................................................47 
3.7.1.5 
Treatment Period (Day 2)............................................................................48 
3.7.1.6 
Treatment Period (Day 3)............................................................................49 
3.7.1.7 
Treatment Period (Day 4 and Day 5) ..........................................................50 
3.7.1.8 
Treatment Period (End-of-trial or at Discontinuation)................................50 
3.7.1.9 
Post-treatment Follow-up Period (7 to 10 days after final 
administration) ............................................................................................51 
3.7.1.10 
Follow-up ....................................................................................................51 
3.7.2 
Prior and Concomitant Medication .................................................................51 
3.7.3 
Efficacy Assessments .....................................................................................52 
3.7.3.1 
Body Weight ...............................................................................................52 
3.7.3.2 
Congestive Symptoms (Lower Limb Edema, Other Edema, Jugular 
Venous Distension, Pulmonary Rales, Third Cardiac Sound, and 
Hepatomegaly) ............................................................................................52 
3.7.3.3 
Chest X-ray (Cardiothoracic Ratio and Pulmonary Congestion) ................53 
3.7.3.4 
NYHA Classification ..................................................................................54 
3.7.4 
Safety Assessments .........................................................................................54 
3.7.4.1 
Adverse Events............................................................................................54 
3.7.4.2 
Clinical Laboratory Assessments ................................................................54 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
10 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.7.4.3 
Physical Examination and Vital Signs (Blood Pressure, Pulse Rate, 
and Body Temperature)...............................................................................55 
3.7.4.4 
12-lead Electrocardiogram ..........................................................................56 
3.7.5 
Pharmacokinetic/pharmacodynamic/pharmacogenomic Assessments ...........57 
3.7.5.1 
Pharmacokinetic Assessments ....................................................................57 
3.7.5.1.1 
Pharmacokinetic Blood Samples .............................................................57 
3.7.5.2 
Pharmacodynamic Assessments .................................................................58 
3.7.5.2.1 
Clinical Laboratory Tests for Pharmacodynamic Analysis (Serum 
Sodium Concentration, Serum Potassium Concentration, Serum 
Osmolality, Biomarkers, Daily Urine Sodium Excretion, Daily 
Urine Potassium Excretion, and Urine Osmolality) ................................58 
3.7.5.2.2 
Daily Urine Volume ................................................................................59 
3.7.5.2.3 
Daily Fluid Intake ....................................................................................60 
3.7.5.2.4 
Daily Fluid Balance .................................................................................60 
3.7.5.3 
Pharmacogenomic Assessments .................................................................60 
3.7.5.3.1 
DNA Storage ...........................................................................................60 
3.7.6 
End of Trial .....................................................................................................62 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures ......................................62 
3.8.1 
Entire Trial or Treatment Arms ......................................................................62 
3.8.2 
Individual Site .................................................................................................63 
3.8.3 
Individual Subject Discontinuation ................................................................63 
3.8.3.1 
Treatment Discontinuation ..........................................................................63 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation ...............................64 
3.8.3.3 
Withdrawal of Consent ...............................................................................64 
3.8.3.4 
Procedures to Encourage Continued Trial Participation .............................66 
3.9 
Screen Failures ..................................................................................................66 
3.10 
Definition of Completed Subjects .....................................................................66 
3.11 
Definition of Subjects Lost to Follow-up ..........................................................67 
3.12 
Subject Compliance ...........................................................................................67 
3.13 
Protocol Deviations ...........................................................................................68 
4 
Restrictions .......................................................................................... 69 
4.1 
Prohibited Medications......................................................................................69 
4.2 
Restricted Concomitant Drugs, etc. ...................................................................70 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
11 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
5 
Reporting of Adverse Events ............................................................. 71 
5.1 
Definitions .........................................................................................................71 
5.2 
Eliciting and Reporting Adverse Events ...........................................................73 
5.3 
Immediately Reportable Events ........................................................................74 
5.4 
Potential Drug-Induced Liver Injury .................................................................74 
5.5 
Pregnancy ..........................................................................................................74 
5.6 
Procedure for Breaking the Blind ......................................................................76 
5.7 
Follow-up of Adverse Events After Treatment Period .....................................76 
5.7.1 
Follow-up of Nonserious Adverse Events ......................................................76 
5.7.2 
Follow-up of Serious Adverse Events ............................................................77 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact ..................................................................................77 
6 
Pharmacokinetic/pharmacodynamic/pharmacogenomic 
Analysis ................................................................................................ 77 
6.1 
Pharmacokinetics...............................................................................................77 
6.1.1 
Pharmacokinetic Analysis Set ........................................................................77 
6.1.2 
Pharmacokinetic Analysis ..............................................................................78 
6.2 
Pharmacodynamics ............................................................................................79 
6.3 
Pharmacokinetics/Pharmacodynamics ..............................................................79 
6.4 
Pharmacogenomics ............................................................................................79 
7 
Statistical Analysis .............................................................................. 80 
7.1 
Sample Size .......................................................................................................80 
7.2 
Datasets for Analysis .........................................................................................80 
7.3 
Handling of Missing Data .................................................................................80 
7.4 
Analysis of Efficacy Endpoints .........................................................................80 
7.4.1 
Body Weight ...................................................................................................80 
7.4.2 
Congestive Symptoms ....................................................................................81 
7.4.2.1 
Lower Limb Edema, Other Edema, and Pulmonary Congestion 
(Chest X-ray Finding) .................................................................................81 
7.4.2.2 
Jugular Venous Distension, Hepatomegaly, and Cardiothoracic Ratio ......81 
7.4.2.3 
Pulmonary Rales and Third Cardiac Sound ................................................81 
7.4.3 
NYHA Classification ......................................................................................82 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
12 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
7.5 
Analysis of Demographic and Baseline Characteristics....................................82 
7.6 
Safety Analysis ..................................................................................................82 
7.6.1 
Adverse Events ...............................................................................................82 
7.6.2 
Clinical Laboratory Data ................................................................................83 
7.6.3 
Vital Signs Data ..............................................................................................83 
7.6.4 
Electrocardiogram Data ..................................................................................83 
8 
Management of Investigational Medicinal Product ........................ 83 
8.1 
Packaging and Labeling ....................................................................................83 
8.2 
Storage ...............................................................................................................84 
8.3 
Accountability ...................................................................................................84 
8.4 
Returns and Destruction ....................................................................................84 
8.5 
Reporting of Product Quality Complaints .........................................................84 
8.5.1 
Eliciting and Reporting Product Quality Complaints .....................................85 
8.5.2 
Information Required for Reporting Product Quality Complaints .................85 
8.5.3 
Return Process for Product Quality Complaints .............................................86 
8.5.4 
Assessment/Evaluation ...................................................................................86 
9 
Records Management ......................................................................... 86 
9.1 
Source Documents .............................................................................................86 
9.2 
Data Collection ..................................................................................................86 
9.3 
File Management at the Trial Site .....................................................................87 
9.4 
Records Retention at the Trial Site....................................................................87 
10 
Quality Control and Quality Assurance ........................................... 88 
10.1 
Monitoring .........................................................................................................88 
10.2 
Auditing .............................................................................................................88 
11 
Ethics and Responsibility ................................................................... 88 
12 
Confidentiality .................................................................................... 89 
13 
Amendment Policy .............................................................................. 89 
14 
Publication Authorship Requirements ............................................. 90 
15 
References ............................................................................................ 91 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
13 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
List of In-text Tables 
Table 2.3-1 
Pharmacokinetic Parameters (Mean ± Standard Deviation) of 
Plasma Tolvaptan Concentration in Healthy Adults After 
Administration of Intravenous OPC-61815 and Oral 
Tolvaptan .......................................................................................26 
Table 2.3-2 
Daily Urine Volume (Mean ± Standard Deviation) of Healthy 
Adults After Administration of Intravenous OPC-61815 and 
Oral Tolvaptan ...............................................................................27 
Table 2.3-3 
Daily Urine Volume (Mean ± Standard Deviation) of Healthy 
Adults Following Intravenous Administration of OPC-61815 
at a Dose of 7.5 mg and 15 mg Over 1 Minute, 5 Minutes, 
and 2 Hours ....................................................................................29 
Table 2.3-4 
tmax of Tolvaptan Following Intravenous Administration of 
OPC-61815 at a Dose of 7.5 mg and 15 mg Over 1 Minute, 5 
Minutes, and 2 Hours .....................................................................31 
Table 2.3-5 
Simulated Pharmacokinetic Parameters of Tolvaptan 
Following Intravenous Administration of OPC-61815 at a 
Dose of 8 mg for 1 Minute, 5 Minutes, 1 Hour, and 2 Hours ........31 
Table 3.1-1 
Treatment Groups and Sample Size ...............................................32 
Table 3.2-1 
Dose Levels and Formulations per Group .....................................35 
Table 3.4.2-1 
Inclusion Criteria ...........................................................................37 
Table 3.4.3-1 
Criteria for Enrollment in the Treatment Period (Inclusion 
Criteria of Run-in Period) ..............................................................38 
Table 3.4.4-1 
Exclusion Criteria ..........................................................................39 
Table 3.5.4-1 
Rationale for Endpoints .................................................................41 
Table 3.7-1 
Schedule of Observations/Tests and Assessments .........................43 
Table 3.7-2 
Blood Sampling Schedule for Plasma Drug Concentration 
Measurement ..................................................................................44 
Table 3.7.1.4-1 
Tests on Day 1, Their Scheduled Time Points, and Blood 
Sampling Time Points After IMP Administration .........................48 
Table 3.7.3.2-1 
Scale for Lower Limb Edema ........................................................52 
Table 3.7.3.3-1 
Scale of Pulmonary Congestion .....................................................53 
Table 3.7.3.4-1 
NYHA Classification .....................................................................54 
Table 3.7.4.2-1 
Clinical Laboratory Assessments ...................................................55 
Table 3.7.5.2.1-1 
Pharmacodynamic Laboratory Tests..............................................59 
Table 4.1-1 
Prohibited Concomitant Drugs ......................................................69 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
14 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Table 4.1-2 
Drugs and Food That Induce or Inhibit CYP3A4 ..........................70 
Table 4.2-1 
Restricted Concomitant Drugs and Therapies ...............................71 
Table 7.4.2.1-1 
Response of Lower Limb Edema, Other Edema, and 
Pulmonary Congestion ...................................................................81 
 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
15 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
List of In-text Figures 
Figure 2.3-1 
Time Course of Urine Excretion Rate After Intravenous 
Administration of OPC-61815 at a Dose of 7.5 mg and 15 mg 
Over 1 Minute, 5 Minutes, and 2 Hours ........................................30 
Figure 3.1-1 
Trial Design Schematic ..................................................................34 
 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
16 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
List of Appendices 
Appendix 1 
Handling and Shipment of Bioanalytical Samples ........................92 
Appendix 2 
Protocol Amendment(s)/Administrative Change(s) ......................94 
 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
17 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
List of Abbreviations and Definitions of Terms 
List of Abbreviations 
Abbreviation Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AVP 
Arginine vasopressin 
BMI 
Body mass index 
BNP 
Brain natriuretic peptide 
cAMP 
Cyclic adenosine 3’,5’-monophosphate 
CIOMS 
Council for International Organizations of Medical Science 
CRF 
Case report form 
CK (CPK) 
Creatine kinase 
CYP 
Cytochrome P450 
DILI 
Drug Induced Liver Injury 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EU 
European Union 
GCP 
Good Clinical Practice 
γ-GTP 
γ-Glutamyltransferase 
hCG 
Human chorionic gonadotropin 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICD 
Implantable Cardioverter Defibrillator 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
IWRS 
Interactive Web Response System 
LDH 
Lactic dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NYHA 
New York Heart Association 
OPC 
Otsuka Pharmaceutical Co. 
PAP 
Prostatic acid phosphatase 
PQC 
Product quality complaint 
SAE 
Serious adverse event 
SIADH 
Syndrome of inappropriate secretion of antidiuretic hormone 
TEAE 
Treatment-emergent adverse event 
TRACP-5b 
Tartrate-resistant acid phosphatase 5b 
ULN 
Upper limit of normal 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
18 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
WOCBP 
Women of childbearing potential 
 
List of Pharmacokinetic Parameters 
Abbreviation/ 
Term 
Unit 
Spelled-out Form or Definition 
AUC∞ 
ng·h/mL 
Area under the concentration-time curve from time zero to infinity 
AUC24h 
ng·h/mL 
Area under the concentration-time curve from time zero to 24 hours 
AUCt 
ng·h/mL 
Area under the concentration-time curve calculated to the last 
observable concentration at time t 
AUC_%Extrap 
% 
Percentage of AUC due to extrapolation from tlast to infinity [(AUC∞ 
− AUCt)/AUC∞ × 100] 
C24h 
ng/mL 
Concentration of drug in the plasma at 24 hours 
CL 
L/h 
Total body clearance of drug from the plasma 
CL/BW 
L/h/kg 
CL/normalized in body weight 
CL/F 
L/h 
Apparent clearance of drug from plasma after extravascular 
administration 
CL/F/BW 
L/h/kg 
CL/F normalized for body weight 
Cmax 
ng/mL 
Maximum (peak) plasma concentration of the drug 
λz 
h-1 
Apparent terminal-phase disposition rate constant (first-order) 
R5,ac(C24h) 
 
Accumulation ratio of 5th dose to first dose at regular administration 
for C24h 
t1/2,z 
h 
Terminal-phase elimination half-life 
tlast 
h 
Time of last measurable (positive) concentration 
tmax 
h 
Time to maximum (peak) plasma concentration 
 
 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
19 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
1 
Introduction 
Tolvaptan is an arginine vasopressin V2 receptor antagonist synthesized by Otsuka 
Pharmaceutical Co., Ltd. (Hereinafter Otsuka Pharmaceutical). It specifically inhibits the 
binding of arginine vasopressin (AVP) to the V2 receptor in the distal nephron to increase 
water excretion without affecting electrolyte excretion (aquaretic effect). For typical 
symptoms of congestive heart failure (CHF) include dyspnea, orthopnea, and jugular 
venous distension,1 diuretics are widely used in the treatment of these symptoms.2,3 
Conventional diuretics (mainly loop diuretics) exert their diuretic effect by increasing 
electrolyte excretion in the urine. This mechanism of action makes them difficult to be a 
therapeutic option for patients with decreased serum electrolyte levels. Because 
conventional diuretics can also impair renal function at high dose levels, dose increase is 
not always an option even when adequate response is not obtained. In contrast, a greater 
diuretic effect can be expected with tolvaptan because of its different mechanism of 
action compared with other conventional diuretics. Moreover, tolvaptan does not lower 
serum electrolyte levels and has little effect on renal function, making it an option for 
patients who are not suitable for dose increase or prolonged treatment with conventional 
diuretics. 
In Japan, tolvaptan was approved in 2010 under the trade name of Samsca® tablets for 
the indication of “volume overload in heart failure when adequate response is not 
obtained with other diuretics (eg, loop diuretics).” In 2013, a new indication of “body 
fluid retention in hepatic cirrhosis when adequate response is not obtained with other 
diuretics (eg, loop diuretics)” was approved. In 2014, another indication of “control of the 
progression of autosomal dominant polycystic kidney disease with increased renal 
volume and rapid renal volume growth” was granted for the drug. Outside Japan, in 2009, 
tolvaptan was approved in the United States for “treatment of hyponatremia with normal 
fluid volume or clinically significant volume overload in patients with heart failure or 
syndrome of inappropriate antidiuretic hormone secretion (SIADH)” and in Europe for 
“hyponatremia secondary to SIADH.” In 2015, an additional indication of “control of the 
progression of rapidly progressive autosomal dominant polycystic kidney disease with 
stage 1 to 3 chronic renal failure” was granted in Europe. Tolvaptan has been approved in 
over 40 countries/regions. 
Tolvaptan is administered to patients in clinical settings as an oral aquaretic and provides 
a useful treatment option for heart failure patients who have persistent fluid retention 
despite treatment with other conventional diuretics. However, aquaretic drugs that have 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
20 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
similar effects to tolvaptan and can be administered intravenously are needed for heart 
failure patients when oral administration is not feasible/desirable, eg, due to impaired 
consciousness, decreased absorption of oral tablets due to edema of the gastrointestinal 
tract associated with central venous pressure elevation caused by heart failure 
(gastrointestinal oedema), oxygen therapy, or an impaired swallowing reflex in elderly 
patients. Tolvaptan is not readily soluble in water and not suited for development as an 
injection. Otsuka Pharmaceutical therefore synthesized the new intravenous aquaretic 
OPC-61815. OPC-61815 is a compound with improved water solubility achieved by 
phosphorylation of the hydroxyl group in the benzazepine ring of tolvaptan, AVP V2 
receptor antagonist. When administered, the phosphate ester of OPC-61815 is hydrolyzed 
by alkali and acid phosphatase in the body and tolvaptan forms. OPC-61815 is under 
development with the expectation that the compound will be effective in the treatment of 
“volume overload in heart failure when adequate response is not obtained with other 
diuretics (eg, loop diuretics).” 
So far, the following three phase 1 trials of OPC-61815 have been completed in healthy 
adult male subjects: single intravenous dose trial (263-08-001), repeated intravenous dose 
trial (263-09-001), and trial investigating the rate of intravenous administration (263-10-
005). Based on the results of these trials, the present trial has been planned to investigate 
the dose of OPC-61815 intravenous injection achieving exposure equivalent to that with 
tolvaptan 15-mg oral tablet. 
1.1 
Nonclinical Data 
In a receptor-binding study using [3H]-AVP as a labeled ligand, OPC-61815 exhibited 
affinity for the human AVP V2 receptor (Ki value: 6.13 ± 1.34 nM), but that affinity was 
about 1/14 that of the primary active metabolite tolvaptan (Ki value: 0.43 ± 0.06 nM). 
OPC-61815 also showed weak affinity for human AVP V1a receptor (Ki value: 54.2 ± 
16.8 nM), only 1/4 that of tolvaptan (Ki value: 12.3 ± 0.80 nM). Like tolvaptan, OPC-
61815 does not show affinity for human AVP V1b receptor. OPC-61815 and tolvaptan 
showed an antagonistic action against V2 receptor in HeLa cells expressing human AVP 
V2 receptor by inhibiting the production of cyclic adenosine 3’,5’-monophosphate 
(cAMP) by AVP. However, neither OPC-61815 nor tolvaptan induced any increase in 
cAMP production by itself, indicating that they possess no intrinsic V2 receptor agonistic 
activity. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
21 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Conscious rats given a single intravenous administration of OPC-61815 (0.1275 to 
12.75 mg/kg) showed a dose-dependent increase in urine volume and decrease in urine 
osmolality. These changes were not attenuated with 7-day repeated dosing. Beagle dogs 
given single intravenous administration of OPC-61815 (0.1275 to 3.825 mg/kg) showed a 
dose-dependent increase in urine volume and decrease in urine osmolality. Free water 
clearance was dose-dependently increased in the dogs, indicating OPC-61815 is an 
aquaretic agent which increases free water excretion. Dogs given a single intravenous 
administration of OPC-61815 showed an increase in plasma AVP concentration without 
increase in plasma renin activity. This showed that, unlike furosemide, OPC-61815 does 
not activate the renin-angiotensin system. 
Histamine-induced vascular hyperpermeability model rats showed a dose-dependent 
increase in urine volume and decrease in urine osmolality after a single intravenous 
administration of OPC-61815 (0.3825 to 3.825 mg/kg, 2 hours before histamine dosing), 
with a dose-dependent suppression of the area of pigment leakage at the histamine 
administration site. In a carrageenin-induced paw edema model, development of paw 
edema was dose-dependently inhibited after a single intravenous administration of OPC-
61815 (1.275 to 12.75 mg/kg, 1 hour before carrageenin dosing). 
In hyponatremia model rats, plasma concentration which was once lowered increased as 
the intravenous administration dose of OPC-61815 was increased (0.255 to 5.1 mg/kg). 
Water content in the brain and heart was increased due to hyponatremia, but it was 
improved after OPC-61815 administration. 
These results show that intravenous administration of OPC-61815 demonstrated the 
aquaretic actions, suggesting that OPC-61815 can be expected to provide clinical efficacy 
in the treatment of various diseases associated with volume expansion due to abnormal 
water metabolism such as hyponatremia and edematous disorders. 
Please refer to the Investigator’s Brochure (IB) for more detailed information. 
1.2 
Clinical Data 
(1) Single Intravenous Dose Trial in Healthy Adult Males (Phase 1) (263-08-001) 
In the phase 1 single intravenous dose trial (263-08-001), 54 healthy adult male subjects 
were given a single intravenous administration (over 5 minutes) of OPC-61815 injection 
0.3, 1, 3, 7.5, 15, or 30 mg or placebo. The plasma concentration of OPC-61815 free form 
reached a peak between the completion of injection and 0.020 hour after injection 
[median time to maximum (peak) plasma concentration (tmax)] and quickly decreased to 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
22 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
below the lower limit of quantitation (46.2 ng/mL) by 8 hours postdose in every dose 
group. The peak plasma concentration (Cmax), area under the concentration-time curve 
from time zero to infinity (AUC∞), and area under the concentration-time curve 
calculated to the last observable concentration at time t (AUCt) increased with the dose 
increase. The mean terminal-phase elimination half-life (t1/2,z) was 0.63 to 1.7 hours. 
Tolvaptan rapidly appeared in the plasma following intravenous administration of OPC-
61815, with the plasma concentration peaking between 0.5 and 1.0 hour postdose and 
then decreasing to below the lower limit of quantitation (2.00 ng/mL) by 72 hours 
postdose in every dose group. The Cmax, AUC∞, and AUCt all increased dose-
dependently, and the mean t1/2,z was between 2.2 and 5.7 hours. A dose-dependent 
increase in urine volume was observed following a single intravenous administration of 
OPC-61815 injection 3 to 30 mg. There was little change in urine electrolyte excretion. 
Serum sodium concentration and serum osmolality increased, but there were no changes 
in serum potassium concentration. In terms of safety, all adverse events (AEs) reported in 
subjects treated with OPC-61815 were mild and resolved without treatment or with 
palliative treatment. 
(2) Repeated Intravenous Dose Trial in Healthy Adult Males (Phase 1) (263-09-001) 
In the phase 1 repeated intravenous dose trial (263-09-001), 36 healthy adult male 
subjects were given a single intravenous administration of OPC-61815 injection 1.25, 5, 
or 20 mg or placebo, followed by repeated intravenous doses (over 1 minute) for 7 days 
after a 1-day washout. No accumulation of OPC-61815 free form or its main active 
metabolite (tolvaptan) was seen. The area under the concentration-time curve (AUC) and 
Cmax of both OPC-61815 free form and tolvaptan increased dose-dependently. During 
once-daily 7-day repeated intravenous administration of OPC-61815 injection 5 mg and 
20 mg, an increase in urine volume was observed. However, the rate of increase did not 
accelerate during repeated administration. In terms of safety, AEs including feeling 
abnormal, pruritus, and erythema were reported frequently during and immediately after 
administration of OPC-61815. All the AEs were mild or moderate and subsequently 
resolved without treatment. However, because many of these events were judged to be 
potentially causally related to the investigational medicinal product (IMP) and were not 
reported in subjects treated with oral tolvaptan, it is suspected that OPC-61815 solution 
could be related to the occurrence of these events. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
23 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
(3) Intravenous Dose Trial on Rate of Injection in Healthy Adult Males (Phase 1) 
(263-10-005) 
The intravenous dose trial on rate of injection (263-10-005) was conducted to investigate 
the duration of administration that can avoid the potentially drug-related adverse events 
reported in the phase 1 repeated intravenous dose trial and not reported in subjects treated 
with oral tolvaptan. The trial was also aimed at exploring the cause of those potentially 
drug-related adverse events. Eighteen healthy adult male subjects were given a single 
intravenous administration of OPC-61815 injection 7.5 mg or 15 mg or placebo at 
different administration durations (2 hours, 5 minutes, and 1 minute). The median tmax of 
OPC-61815 free form was 1.8 to 2.0 hours after a 2-hour single intravenous 
administration of OPC-61815. The mean Cmax of OPC-61815 free form after 2-hour 
administration was approximately 70% lower than that after both 5-minute and 1-minute 
administration. The median tmax of tolvaptan after 2-hour administration was 2.3 hours. 
The mean Cmax of tolvaptan was similar across the durations of administration. The rate 
of increase in mean urine volume until 4 hours after a 2-hour single intravenous 
administration of OPC-61815 was lower than that after both 5-minute and 1-minute 
administration. 
In terms of safety, the AEs similar to feeling abnormal, pruritus, and erythema, etc. that 
were frequently reported in the repeated intravenous dose trial (263-09-001) were 
selected as notable AEs. Those notable AEs occurred in 1 out of 12 subjects in the OPC-
61815 groups and in 3 out of 6 subjects in the placebo group after 2-hour administration. 
Any causal relationship between the events and the IMP was ruled out except for the 
pruritus reported in 1 subject of the placebo group. The notable events occurred in 9 out 
of 12 subjects in the OPC-61815 groups and 2 out of 6 subjects in the placebo group after 
5-minute administration. All the events were judged to be related to the IMP. The notable 
events were reported in 10 out of 11 subjects in the OPC-61815 groups and in 4 out of 6 
subjects in the placebo group after 1-minute administration. All the events excluding 
erythema reported once in 1 subject treated with OPC-61815 were judged to be related to 
the IMP. All the AEs potentially causally related to the IMP occurred during or 
immediately after intravenous administration. Most of those events resolved without 
treatment within 10 minutes after the start of IMP administration. Because there were no 
clinically significant changes from baseline in plasma histamine concentration, the cause 
of the notable AEs is unclear. 
Please refer to the IB for more detailed information. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
24 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
1.3 
Known and Potential Risks and Benefits 
OPC-61815 has never been administered to patients with heart failure. No deaths or other 
serious adverse events (SAEs) were reported in the phase 1 trials in healthy adult male 
subjects (263-08-001, 263-09-001, and 263-10-005). Feeling abnormal, feeling hot, 
pruritus, erythema, hyperhidrosis, nausea, epigastric discomfort, and dyspnea were the 
significant AEs reported following bolus intravenous administration (over 1 or 5 minutes) 
of OPC-61815 in Trial 263-09-001 or 263-10-005. Significant AEs were defined as those 
similar to feeling abnormal, pruritus, and erythema, etc. that were reported frequently in 
the repeated intravenous dose trial (263-09-001). 
As noted earlier, OPC-61815 has not previously been administered to patients with heart 
failure. Nevertheless, OPC-61815 should have similar benefits to tolvaptan because, 
when the phosphate ester of OPC-61815 is hydrolyzed by alkali and acid phosphatase in 
the body, tolvaptan forms and acts as an aquaretic agent. Tolvaptan has been shown to 
relieve weight increase and other signs commonly observed in patients with cardiac 
edema (jugular venous distension, hepatomegaly, and lower limb edema). 
In a clinical trial in patients with cardiac edema, the following AEs were frequently 
reported among 437 patients given tolvaptan (in ≥ 2% incidence among tolvaptan-treated 
patients and at a higher frequency than in placebo-treated patients): ventricular 
tachycardia, constipation, dry mouth, diarrhoea, vomiting, thirst, blood urea increased, 
blood uric acid increased, blood creatinine increased, blood potassium increased, blood 
sodium increased, blood glucose increased, blood urine present, platelet count decreased, 
dehydration, hyperkalaemia, dizziness, pollakiuria, renal impairment, and epistaxis. 
Please refer to the IB for more detailed information. 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
Tolvaptan is approved for oral administration at 15 mg once daily in the treatment of 
“volume overload in heart failure when adequate response is not obtained with other 
diuretics (eg, loop diuretics).” 
OPC-61815 is a compound based on tolvaptan of which the lower water solubility has 
been improved by phosphorylation of the hydroxide of the benzazepine ring. In the body, 
OPC-61815 is considered to be metabolized to tolvaptan via hydrolysis of the phosphate 
ester by alkaline and acid phosphatase, and the formed tolvaptan acts as an aquaretic 
agent. OPC-61815 provides an aquaretic intravenous treatment option for “congestive 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
25 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
heart failure patients with excessive fluid retention despite treatment with other diuretics” 
and should prove useful. We started clinical development of OPC-61815 in heart failure 
patients with persistent fluid retention despite treatment with conventional diuretics for 
the intended indication of “volume overload in heart failure when adequate response is 
not obtained with other diuretics (eg, loop diuretics).” The aquaretic effect of OPC-61815 
is thought to be produced by the active metabolite tolvaptan. Because tolvaptan is widely 
used in heart failure patients who have fluid retention despite treatment with conventional 
diuretics, treating patients with placebo in a clinical trial of OPC-61815 is considered 
unethical. A phase 3 trial of OPC-61815 will therefore investigate the noninferiority of 
OPC-61815 to tolvaptan 15-mg tablet instead of using placebo as control. 
Data in healthy adults show intravenous OPC-61815 at doses of 3 to 30 mg (about half 
the dose levels of tolvaptan tablets) achieves equivalent exposure of tolvaptan and daily 
urine volume to those achieved with oral tolvaptan tablets at doses of 5 to 60 mg. 
However, because OPC-61815 has not previously been administered to heart failure 
patients, the dose-exposure relationships of intravenous OPC-61815 and oral tolvaptan in 
heart failure patients are not yet clear. This phase 2 pharmacology trial has been planned 
to determine the dose of OPC-61815 injection equivalent to tolvaptan 15-mg tablet, 
which is used in clinical setting in heart failure patients with fluid retention despite 
treatment with conventional diuretics. 
Based on the above, we consider the conduct of this trial is scientifically and ethically 
justified. 
2.2 
Justification for DNA storage 
This trial will store deoxyribonucleic acid (DNA) samples on a voluntary basis. Sampling 
for DNA storage will take place only at the trial sites that have agreed to perform 
sampling for DNA storage prior to the trial. DNA samples will be collected only from 
subjects who have given consent to DNA storage in writing. In the questions and answers 
section of the “Clinical trials based on pharmacogenomics” (Notification No. 0930007 of 
the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau issued on 
30 Sep 2008), the Ministry of Health, Labour and Welfare states that collection of DNA 
samples from trial subjects and retention of the samples for genomic/genetic analysis 
related to evaluation of IMPs used in a trial (pharmacokinetics, efficacy, safety, etc.) are 
acceptable provided (1) the target and schedule of analysis are established at the conduct 
of the trial or (2) genomic/genetic analysis is planned although neither its target nor 
schedule has been established at the conduct of the trial. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
26 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
We therefore think storing DNA samples for future analysis of the relationships between 
interindividual differences in the efficacy, safety, or pharmacokinetics of OPC-61815 and 
variations of DNA characteristics (eg, genetic polymorphism) is justified. 
2.3 
Dosing Rationale 
(1) Dose 
Tolvaptan exposure and daily urine volume reported in the single intravenous dose trial 
of OPC-61815 (263-08-0014) and single oral dose trials of tolvaptan (156-95-3025 and 
156-00-0016) in healthy adults are summarized respectively in Table 2.3-1 and Table 2.3-
2. 
At the dose ranges tested (OPC-61815 injection 3, 7.5, 15, and 30 mg and tolvaptan 
tablets 5, 15, 30, and 60 mg), OPC-61815 injection at about half the dose of tolvaptan 
tablets achieved tolvaptan exposure and daily urine volume equivalent to those achieved 
with tolvaptan tablets. 
 
Table 2.3-1 
Pharmacokinetic Parameters (Mean ± Standard Deviation) of 
Plasma Tolvaptan Concentration in Healthy Adults After 
Administration of Intravenous OPC-61815 and Oral Tolvaptan 
Intravenous OPC-61815a 
Oral Tolvaptan 
Dose 
(mg) 
Cmax 
(ng/mL) 
AUCt 
(ng∙h/mL) 
tmax
b 
(h) 
Dose 
(mg) 
Cmax 
(ng/mL) 
AUCt 
(ng∙h/mL) 
tmax
b 
(h) 
3 
(N = 6) 
34.58± 5.420 
155.0 ± 29.76 
1.0 
5c 
(N = 6) 
48.3 ± 16.0 
203.43± 80.47 
1.5e 
7.5 
(N = 6) 
116.7 ± 30.23 
527.5 ± 134.2 
0.5 
15d 
(N = 6) 
135.27 ± 52.58 
645.4 ± 367.0 
2.0 
15 
(N = 6) 
268.8 ± 52.66 
1598 ± 586.6 
1.0 
30d 
(N = 
12) 
213.37 ± 75.75 
1301.5 ± 552.6 
2.0 
30 
(N = 6) 
442.5 ± 64.87 
1980 ± 535.8 
0.5 
60d 
(N = 6) 
315.22 ± 104.89 
2321.4 ± 633.5 
3.0 
aTrial 263-08-001, bMedian, cTrial 156-95-302, dTrial 156-00-001, eMedian calculated from individual 
values (only the mean is provided in the clinical study report of Trial 156-95-302) 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
27 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Table 2.3-2 
Daily Urine Volume (Mean ± Standard Deviation) of Healthy 
Adults After Administration of Intravenous OPC-61815 and 
Oral Tolvaptan 
Intravenous OPC-61815a 
Oral Tolvaptan 
Dose 
(mg) 
Daily Urine Volume 
(mL/24h) 
Dose 
(mg) 
Daily Urine Volume 
(mL/24h) 
Placebo 
(N = 16) 
2687.8 ± 1519.7 
Placeboc 
(N = 14) 
2584.5 ± 1298.4 
3 
(N = 6) 
3752.3 ± 465.2 
5b 
(N = 6) 
2710.8± 363.3d 
7.5 
(N = 5) 
4240.0 ± 756.2 
15c 
(N =6) 
3018.5 ± 729.9 
15 
(N = 6) 
5810.2 ± 1213.4 
30c 
(N = 12) 
5722.9 ± 643.2 
30 
(N = 6) 
7173.7 ± 1582.4 
60c 
(N = 6) 
8751.5 ± 1280.6 
aTrial 263-08-001, bTrial 156-95-302, cTrial 156-00-001, dDaily urine volume was calculated from 
individual values (only the measurements of individual collection periods are provided in the clinical 
study report of Trial 156-95-302) 
 
In Japan, the approved dose and regimen of Samsca tablets, of which active ingredient is 
tolvaptan, is “The usual adult dosage of Tolvaptan is 15 mg once a day orally.” The 
recommended initial dose is 7.5 mg for patients with a serum sodium concentration of 
less than 125 mEq/L and patients in whom a rapid decrease in plasma volume should be 
avoided. Because intravenous administration of OPC-61815 at about half the dose of 
tolvaptan tablets achieved tolvaptan exposure equivalent to tolvaptan tablets in healthy 
adults, this trial will administer OPC-61815 injection at 4 mg, 8 mg (respectively about 
half the tolvaptan tablets 7.5 mg and 15 mg), and 16 mg (double dose of 8 mg), as the 
doses expected to achieve effects equivalent to tolvaptan tablets. 
Liver metabolism of tolvaptan is expected to be decreased in heart failure patients due to 
blood flow in organs and especially in the liver, compared with healthy adults. Also, the 
first-pass metabolism (in the gastrointestinal tract and liver) of tolvaptan tablets may 
differ in healthy adults and heart failure patients. Because of these matters, in heart 
failure patients, OPC-61815 injection at a dose about half that of tolvaptan tablets may 
not reproduce equivalent tolvaptan exposure to tolvaptan tablets as indicated in healthy 
adults. 
Considering that OPC-61815 injection has not previously been administered to heart 
failure patients and also that OPC-61815 injection at a lower dose than indicated in 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
28 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
healthy adults may achieve equivalent tolvaptan exposure to that with tolvaptan 15-mg 
tablet, we decided to administer OPC-61815 injection at 2 mg in addition to at 4 mg, 
8 mg, and 16 mg. 
(2) Regimen 
The once-daily administration of OPC-61815 is selected for this trial because a sufficient 
plasma tolvaptan exposure and daily urine volume had been achieved with the same 
regimen in phase 1 trials in healthy adults (263-08-001, 263-09-001, and 263-10-0057). 
In the repeated dose trial administering OPC-61815 injection intravenously for 1 minute 
(263-09-001), the following AEs not reported in the single dose trial that administered the 
injection for 5 minutes (263-08-001) were reported: feeling abnormal in 9 of 27 subjects, 
pruritus in 5 of 27 subjects, pruritus generalised in 3 of 27 subjects, and erythema in 3 of 
27 subjects. The trial investigating the rate of intravenous injection of OPC-61815 (263-
10-005) administered the drug over 2 hours, 5 minutes, and 1 minute to explore the cause 
of the above AEs and also to investigate the relationships between the events and the rate 
of administration. None of these potentially drug-related adverse events occurred when 
OPC-61815 injection 7.5 mg and 15 mg were administered over 2 hours. 
The results of the trial indicate the risk of the above potentially drug-related adverse 
events may be reduced by administering OPC-61815 with longer administration duration. 
The daily urine volume (mean ± standard deviation) in the trial investigating the rate of 
administration is summarized in Table 2.3-3. 
Daily urine volume was generally consistent regardless of the rate of administration. This 
suggests the diuretic effect 24 hours after administration is not likely to be affected by the 
rate of administration. 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
29 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Table 2.3-3 
Daily Urine Volume (Mean ± Standard Deviation) of 
Healthy Adults Following Intravenous 
Administration of OPC-61815 at a Dose of 7.5 mg 
and 15 mg Over 1 Minute, 5 Minutes, and 2 Hours 
Dose (mg) 
Duration of 
Administration 
Daily Urine Volume (mL/24 h) 
Placebo 
1 minute (N = 6) 
2576.7 ± 1412.2 
5 minutes (N = 6) 
2418.4 ± 764.0 
2 hours (N = 6) 
2272.3 ± 951.5 
7.5 
1 minute (N = 5) 
3276.8 ± 614.1 
5 minutes (N = 6) 
3647.5 ± 828.9 
2 hours (N = 6) 
3353.0 ± 861.8 
15 
1 minute (N = 6) 
5584.8 ± 953.0 
5 minutes (N = 6) 
4818.3 ± 1358.6 
2 hours  (N = 6) 
4765.2 ± 1583.9 
 
Figure 2.3-1 illustrates the time course of urine excretion rate by the rate of 
administration in the trial on the rate of intravenous administration. Table 2.3-4 
summarizes the tmax of plasma tolvaptan by the rate of administration. The initial peak of 
urine excretion rate was observed between 0.75 and 1.25 hours with bolus injection 
(administered for 1 or 5 minutes). With 2-hour administration, it was 2.75 hours. The tmax 
of tolvaptan was 0.5 to 1 hour with bolus injection and 2.3 hours with 2-hour 
administration. The peak urine excretion rate was observed slightly after the tmax, but the 
above results indicate shortening the tmax should achieve an earlier onset of action. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
30 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
 
 
 
Figure 2.3-1 
Time Course of Urine Excretion Rate After Intravenous 
Administration of OPC-61815 at a Dose of 7.5 mg and 15 mg 
Over 1 Minute, 5 Minutes, and 2 Hours 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
31 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
 
Table 2.3-4 
tmax of Tolvaptan Following Intravenous Administration 
of OPC-61815 at a Dose of 7.5 mg and 15 mg Over 1 
Minute, 5 Minutes, and 2 Hours 
 
tmax (h) of Plasma Tolvaptan 
Duration of administration 
Dose 
1 minute 
5 minutes 
2 hours 
7.5 mg 
0.50 
1.00 
2.30 
15 mg 
0.75 
0.50 
2.30 
(Median) 
 
PK models of plasma OPC-61815 and tolvaptan concentration were created using data 
from the prior phase 1 studies (263-08-001, 263-09-001, and 263-10-005) for simulation 
of change in pharmacokinetic parameters of OPC-61815 and tolvaptan by the rate of 
administration. The simulated pharmacokinetic parameters of tolvaptan following 
administration of OPC-61815 injection 8 mg are summarized in Table 2.3-5. The 
simulation showed no significant differences in the AUC24h or Cmax of tolvaptan across 
the duration of administration. This suggests similar effects regardless of the duration of 
administration. However, the observed differences in tmax indicate the duration of 
administration may affect the time to onset of action. The tmax of tolvaptan was 1, 1.5, 
and 2.25 hours after bolus (1 or 5 minutes), 1-hour, and 2-hour intravenous injection of 
OPC-61815, respectively. The difference in tmax between bolus injections, which was 
over 1 hour by 2-hour intravenous injection, was estimated to decrease to about 30 
minutes by 1-hour intravenous injection. The tmax of tolvaptan after administration of 
tolvaptan 15-mg tablet is 2 hours. Therefore, these results suggest that, if OPC-61815 is 
administered intravenously over 1 hour, compared with tolvaptan tablets, an earlier tmax 
of tolvaptan and an earlier onset of action should be achieved. 
Table 2.3-5 
Simulated Pharmacokinetic Parameters of Tolvaptan 
Following Intravenous Administration of OPC-61815 at a 
Dose of 8 mg for 1 Minute, 5 Minutes, 1 Hour, and 2 Hours 
Duration of 
administration 
AUC24h (h∙ng/mL) 
(mean ± standard deviation) 
Cmax (ng/mL) 
(mean ± standard deviation) 
tmax (h) 
(median) 
1 minute 
521.5 ± 141.2 
115.1 ± 24.12 
1 
5 minutes 
531.5 ± 145.5 
115.5 ± 23.86 
1 
1 hour 
521.1 ± 142.6 
109.6 ± 22.07 
1.5 
2 hours 
522.5 ± 144.4 
99.93 ± 20.11 
2.25 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
32 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Early onset of action (eg, for relief of dyspnea) is desired in some patients hospitalized 
with heart failure. This trial will intravenously administer OPC-61815 at 2 mg, 4 mg, 
8 mg, and 16 mg over 1 hour in CHF patients to investigate the dose and regimen of 
OPC-61815 equivalent to once-daily tolvaptan 15-mg tablet. 
2.4 
Trial Objectives 
Primary: To investigate the dose of OPC-61815 injection formulation achieving exposure 
equivalent to that for tolvaptan 15-mg tablet by 1-hour intravenous administration of 
OPC-61815 at 2, 4, 8, or 16 mg once daily or oral administration of tolvaptan 15-mg 
tablet once daily for 5 days in CHF patients with volume overload despite having 
received diuretics other than vasopressin antagonists. 
Secondary: To investigate the efficacy, pharmacokinetics, pharmacodynamics, and safety 
of OPC-61815 in comparison with tolvaptan tablet by 1-hour intravenous administration 
of OPC-61815 at 2, 4, 8, or 16 mg once daily or oral administration of tolvaptan tablet at 
15 mg once daily for 5 days in CHF patients with volume overload despite having 
received diuretics other than vasopressin antagonists. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multicenter, randomized, double-blind, active-controlled (with tolvaptan tablet), 
double-dummy, parallel group comparison trial. Fifty CHF patients with volume overload 
despite having received diuretics other than vasopressin antagonists will be randomly 
assigned to OPC-61815 injection 2 mg, 4 mg, 8 mg, or 16 mg or tolvaptan tablet 15 mg 
group (10 per group) (see Table 3.1-1) to investigate the dose of OPC-61815 injection 
required to achieve exposure equivalent to tolvaptan 15-mg tablet. To account for 
withdrawals, 11 patients per group (total 55 patients) will start IMP administration. 
Table 3.1-1 
Treatment Groups and Sample Size 
Group 
OPC-61815 Dose 
Tolvaptan Dose 
Sample Sizea 
Tolvaptan 15-mg tablet 
0 mg/day 
15 mg/day 
10 
OPC-61815 injection 2 mg 
2 mg/day 
0 mg/day 
10 
OPC-61815 injection 4 mg 
4 mg/day 
0 mg/day 
10 
OPC-61815 injection 8 mg 
8 mg/day 
0 mg/day 
10 
OPC-61815 injection 16 mg 
16 mg/day 
0 mg/day 
10 
aAt least 10 patients per group will complete blood sampling for plasma drug concentration 
measurement by 24 hours after administration on Day 1. 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
33 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
The trial schedule is summarized in Figure 3.1-1. The 3-day period prior to IMP 
administration constitutes the run-in period. The use of diuretics, body weight change, 
and congestive symptoms are evaluated during the run-in period. Only the patients who 
meet the criteria for enrollment in the treatment period (see Table 3.4.3-1) will be 
enrolled to undergo treatment. The patients will receive the IMP once a day for 5 days 
during the treatment period. No change of a diuretic dose or regimen will be allowed 
throughout the run-in period and until the end-of-trial examination on the day after final 
administration in the treatment period. End-of-trial examination will be performed on 
Day 6 (day after final administration) and post-treatment follow-up examination will be 
performed between Days 12 and 15. 
This trial will be conducted using a double-dummy design to maintain blindness. 
Subjects will receive a combination of either OPC-61815 injection and placebo tablet or 
placebo injection and tolvaptan 15-mg tablet. As there will be a difference in appearance 
between the OPC-61815 solution and the placebo solution, the designated non-blinded 
staff at the trial site will prepare the double-blinded IMP. All enrolled patients will be 
admitted and remain hospitalized from the day before the start of the run-in period to the 
end of the treatment period. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
34 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
 
Figure 3.1-1 
Trial Design Schematic 
Note) Each patient who fails to complete 5-day IMP administration for any reason should be asked to 
undergo same tests/examination to those scheduled for the end-of-trial examination (the day after the 
final IMP administration), if possible, and be followed up between 7 and 10 days after the final IMP 
administration. 
 
3.2 
Trial Treatments 
3.2.1 
Dose and Regimen and Duration of Treatment 
The dose levels and formulations for each group are summarized in Table 3.2-1. The 
investigator or subinvestigator will administer either one tolvaptan 15-mg tablet or 
placebo tablet once a day with water, immediately followed by intravenous 
administration of either OPC-61815 injection at 2 mg, 4 mg, 8 mg, or 16 mg or placebo 
for 1 hour (acceptable range: 55 to 65 minutes) according to a separate written procedure 
for IMP administration. Each dose should be administered promptly after the patient 
completes urine sampling (for daily urine volume measurement) after breakfast each day 
during the 5-day treatment period. The time of administration (start time of 
administration) on Day 2 and later should be not more than 20 minutes before or after the 
time of administration (start time of administration) on Day 1. After confirming each 
-3
-2
-1
1
2
3
4
5
6
12 to 15
(Day)
Follow-up
(7 to 10 days after
final administration)
Screening examination
Informed consent (start date of trial)
Start of IMP administration
End of IMP administration
End-of-trial examination (the day after final
administration)
Post-treatment follow-up
(Date of final observation/trial completion)
Inpatient/Outpatient
Diuretics: Modification of the dose and regimen is not allowed
Hospitalized (from Day -4 to Day 6, 10 days)
Tolvaptan 15-mg tablet
OPC-61815 injection 2, 4, 8, or 16 mg
-7 to -4
Screening period
Run-in period
(3 days)
Treatment period
(6 days)


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
35 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
dose has been administered, the investigator or subinvestigator documents the start and 
finish time of administration (for injection) or the date and time of administration (for 
tablet) in source documents and case report form (CRF). The IMP is to be administered 
even if the patient fails to eat breakfast that day. 
Table 3.2-1 
Dose Levels and Formulations per Group 
Group 
OPC-61815 
Dose 
Formulation(s) (per day) 
Tolvaptan 15-mg tablet 
0 mg/day 
1 vial of placebo injection, 1 tolvaptan 15-mg tablet 
OPC-61815 injection 2 mg 
2 mg/day 
1 vial of OPC-61815 injection 2 mg, 1 placebo tablet 
OPC-61815 injection 4 mg 
4 mg/day 
1 vial of OPC-61815 injection 4 mg, 1 placebo tablet 
OPC-61815 injection 8 mg 
8 mg/day 
1 vial of OPC-61815 injection 8 mg, 1 placebo tablet 
OPC-61815 injection 16 mg 
16 mg/day 
1 vial of OPC-61815 injection 16 mg, 1 placebo tablet 
 
[Rationale for duration of treatment] 
The primary endpoint of this trial is tolvaptan exposure (Cmax and AUC24h on Day 1 of the treatment 
period). Tolvaptan does not accumulate and repeated administration of the drug is thought to demonstrate a 
blood concentration-time profile similar to that after single administration. Because of this, tolvaptan 
exposure can be evaluated based on a single day of treatment. Body weight is included in the efficacy 
secondary endpoints. The late phase 2 trial (156-03-001) and phase 3 trial (156-06-002) of tolvaptan in 
CHF patients administered the drug for 7 days. The difference in body weight change between the 
tolvaptan 15-mg tablet group and placebo group was almost consistent from the fourth day of treatment in 
the phase 2 trial (156-03-001) and largest after 6 days of treatment in the phase 3 trial (156-06-002). 
Throughout treatment, the body weight of patients in the tolvaptan 15-mg group was statistically 
significantly decreased compared with that in the placebo group. Effects of the IMP on body weight can 
therefore be evaluated based on treatment over a 5-day period. Based on the above, a 5-day treatment 
period should be appropriate for this trial. 
 
3.2.2 
IMP Preparation 
The person responsible for IMP preparation (non-blinded staff) designated at the trial site 
will prepare the IMP before use according to a specified procedure. The person 
responsible for IMP preparation (non-blinded staff) is obliged to keep confidential all 
information acquired through IMP preparation. 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Description of Population 
Fifty-five Japanese male or female CHF patients with volume overload (lower limb 
edema, pulmonary congestion, or jugular venous distension) despite having received 
diuretics other than vasopressin antagonists, age 20 to 85 years, inclusive, will be 
enrolled in the trial (11 patients per group to start treatment). All subjects must be 
available for hospitalization from the day before the start of the run-in period to the end 
of the treatment period and also be able to swallow the tolvaptan tablet. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
36 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.3.2 
Subject Selection and Numbering 
A subject identifier (subject ID) (site number [3 digits] + ‘S’ + subject number [5 -digit 
in-site serial number]) will be assigned to each consented subject. The site number (3 
digits) will be designated by the sponsor. The subject number (5-digit in-site serial 
number) will start from “00001” and be assigned to each subject in the order of consent 
per trial site. The trial site will create and keep a list of all consented subjects and their 
subject identifiers. 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Written informed consent will be freely obtained from all subjects. Consent will be 
documented on a written informed consent form (ICF). Any patient who has given 
consent to participate in the trial may still refuse to provide samples for DNA storage 
without having to withdraw from the trial. The ICF will be approved by the same 
institutional review board (IRB) that approves this protocol. 
Each ICF will comply with the ICH (International Council for Harmonisation) Good 
Clinical Practice (GCP) Guideline8 and local regulatory requirements. 
Investigator or subinvestigator may discuss trial availability and the possibility for entry 
with a potential subject without first obtaining consent. However, informed consent must 
be obtained and documented before initiation of any procedures that are performed solely 
for the purpose of determining eligibility for this trial, including withdrawal from current 
medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care. 
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator or subinvestigator, the IRB-approved 
written ICF will be signed and dated by both the subject and the person obtaining consent 
(investigator or subinvestigator). If a study collaborator has provided a supplemental 
explanation, the IRB approved written ICF will be signed and dated by the study 
collaborator. The subject will receive a copy of the signed ICF; the original shall be kept 
on file by the investigator or subinvestigator. 
Subjects may be asked to sign additional ICFs if the protocol is amended to significantly 
add or change procedures. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
37 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.4.2 
Inclusion Criteria 
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1. 
Table 3.4.2-1 
Inclusion Criteria 
1 
Subjects who are currently on treatment with any of the following oral diuretics (or are scheduled 
to start treatment with the drugs during the run-in period) 
• 
Loop diuretics equivalent to furosemide tablet or fine granules at a dose of 40 mg/day or 
higher 
• 
Concomitant use of a loop diuretic and a thiazide diuretic (including thiazide analogs) at any 
dose 
• 
Concomitant use of a loop diuretic and an aldosterone antagonist or potassium-sparing diuretic 
agent at any dose 
Note) The permissible types and doses of diuretics are as follows: 
a) Loop diuretics equivalent to furosemide tablet or fine granules at a dose of 40 mg/day or 
higher 
Bumetanide tablet, 1 mg; azosemide, 60 mg; torasemide, 8 mg 
b) Thiazide diuretics (including thiazide analogs) 
Hydrochlorothiazide tablet, trichlormethiazide tablet, benzylhydrochlorothiazide tablet, 
mefruside tablet 
c) Aldosterone antagonist or potassium-sparing diuretic agent 
Spironolactone tablet/fine granules, triamterene capsule 
2 
Subjects with CHF in whom lower limb edema, pulmonary congestion, and/or jugular venous 
distension due to volume overload is present. When pulmonary congestion is confirmed by chest 
X-ray performed within 14 days before consent, the subject may be included in the trail 
3 
Male or female subjects age 20 to 85 years, inclusive, at the time of informed consent 
4 
Subjects who are currently hospitalized or who are able to be hospitalized from the day before the 
run-in period (Day −4) to the end of the treatment period 
5 
Subjects who are capable of taking oral tablets 
6 
Subjects capable of giving consent 
 
 
[Rationale for inclusion criteria] 
1 
This criterion is set to include patients who are using loop diuretics equivalent to furosemide at 
dose of 40 mg/day or higher, a combination of a loop diuretic(s) and thiazide diuretic(s), or a 
combination of a loop diuretic(s) and aldosterone antagonist(s) because these are commonly used 
for the treatment of cardiac edema. 
2 
Common signs of volume overload include jugular venous distension, hepatomegaly, and third 
cardiac sound, etc. in addition to lower limb edema and pulmonary congestion. Lower limb edema, 
pulmonary congestion, and jugular venous distension are included in the criterion because these are 
less likely to be caused by factors other than volume overload compared with other signs and also 
because they were observed in many patients in the late phase 2 trial (156-03-001) and phase 3 trial 
(156-06-002) of tolvaptan in CHF patients. 
3 
The lower limit is the age limit of adults who have capability to be responsible for consent. The 
upper limit of 85 is set because most CHF patients are elderly and also for safety reasons. 
4 
This criterion is set to include subjects who are able to be hospitalized to ensure accurate evaluation 
and for their own safety. 
5 
This criterion is set because tolvaptan tablets are used as control. 
6 
This criterion is set to ensure ethical conduct of the trial. 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
38 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.4.3 
Criteria for Enrollment in the Treatment Period (Inclusion Criteria 
of Run-in Period) 
Subjects who meet the criteria for enrollment in the treatment period (shown in Table 
3.4.3-1) and are judged by the investigator or subinvestigator to be suitable for 
enrollment in the treatment period will be enrolled for appropriate efficacy evaluation. 
Table 3.4.3-1 
Criteria for Enrollment in the Treatment Period (Inclusion 
Criteria of Run-in Period) 
7 
Subjects with either lower limb edema, jugular venous distension (on Day −1 of the run-in period), 
or pulmonary congestion (confirmed by chest X-ray performed during the run-in period) 
8 
Subjects who are given diuretic agents with no change in dose or regimen during the run-in period  
9 
Subjects with no more than 1.0 kg change in body weight over the 2 days (Day −2 to Day −1 of the 
run-in period) prior to IMP administration 
 
 
[Rationale for inclusion criteria of run-in period] 
7 
This criterion is set as these signs of excessive volume overload are expected to be relieved by the 
aquaretic effect of OPC-61815. 
8 
This criterion is set to enroll subjects who have persistent volume overload despite having been 
treated with a common diuretic regimen other than vasopressin antagonists. 
9 
This criterion is set to ensure that subjects who have a constant volume overload are enrolled for 
efficacy evaluation of OPC-61815. 
 
3.4.4 
Exclusion Criteria 
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.4-1. 
A subject excluded as a result of falling under any of the exclusion criteria may be 
rescreened if any changes in the condition resulting in falling under the exclusion criteria 
are observed. For rescreening, the subject will be asked to follow the procedure described 
in Section 3.9. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
39 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Table 3.4.4-1 
Exclusion Criteria 
1 
Subjects with acute heart failure 
2 
Subjects with mainly noncardiogenic congestive symptoms 
3 
Subjects who are on an ventricular assist device 
4 
Subjects who have the following diseases, complication, or conditions: 
• 
Subjects who are suspected of having hypovolemia 
• 
Hypertrophic cardiomyopathy (excluding dilated phase) 
• 
Valvular disease with significant valvular stenosis; or 
• 
Hepatic encephalopathy with difficulty in adequate fluid intake 
5 
Subjects who have experienced acute myocardial infarction within 30 days prior to the screening 
examination 
6 
Subjects with definite diagnosis of active myocarditis or amyloid cardiomyopathy 
7 
Subjects who have the following diseases, complication, or conditions: 
• 
Poorly controlled diabetes mellitus 
• 
Anuria 
• 
Dysuria associated with urinary tract obstruction, calculus, or tumor 
8 
Subjects who have the following history of disease: 
• 
History of sustained ventricular tachycardia or ventricular fibrillation within 30 days prior to 
the screening examination among subjects without an implantable cardioverter defibrillator 
• 
History of cerebrovascular disease (excluding asymptomatic cerebral infarction) within 6 
months prior to the screening examination 
• 
Subjects with a history of hypersensitivity to any of ingredients of OPC-61815 or tolvaptan 
• 
History of hypersensitivity or idiosyncratic reaction to benzazepines or benzazepine 
derivatives such as mozavaptan hydrochloride and benazepril hydrochloride 
9 
Subjects who are severely obese (body mass index [BMI], body weight [kg]/height [m]2 exceeding 
35 kg/m2) 
10 
Subjects with supine systolic blood pressure of <90 mmHg 
11 
Subjects with any of the following laboratory test abnormalities: 
Total bilirubin, >3.0 mg/dL; serum creatinine, >3.0 mg/dL; serum sodium >147 mEq/L; serum 
potassium, >5.5 mEq/L 
12 
Subjects with concurrent symptoms or history of hepatic impairment (including subjects with 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at the screening examination 
exceeding 3 times the upper limit of normal) 
13 
Subjects who are unable to sense thirst or who have difficulty with fluid intake 
14 
Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving 
investigational medicinal product (IMP) 
15 
Sexually active males or women of childbearing potential (WOCBP) who do not agree to practice 
birth control or remain abstinent during the trial and for 30 days after the last administration of IMP  
16 
Subjects treated with another IMP within 30 days prior to the screening examination 
17 
Subjects who are otherwise judged to be ineligible by the investigator or subinvestigator 
 
Nonchildbearing potential is defined as male and female subjects who are surgically 
sterile (ie, male subjects who have undergone bilateral orchidectomy and female subjects 
who have undergone bilateral oophorectomy and/or hysterectomy) and female subjects 
who have been postmenopausal for at least 12 consecutive months. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
40 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Subjects must agree to restrictions as described in Section 4. 
[Rationale for exclusion criteria] 
1 
This criterion is set because subjects must be able to swallow the tolvaptan tablet (control) and 
because acute onset or worsening of symptoms can make trial continuation difficult. 
2 
This criterion is set because OPC-61815 is intended for patients with volume overload due to 
CHF. 
3 
This criterion is set to avoid potential influence on efficacy and safety evaluation in the trial. 
4 
This criterion is set because excessive diuretic therapy is undesirable. 
5, 6 
These criteria are set for safety reasons. 
7 
This criterion is set for safety reasons and because such subjects are considered ineligible for 
participation in the trial. 
8 
This criterion is set for safety reasons. 
9 
This criterion is set because efficacy evaluation will be difficult in such subjects. 
10 
This criterion is set because diuresis may decrease blood pressure. 
11 to 13 
These criteria are set for safety reasons. 
14 to 17 
These criteria are set for general safety and ethical considerations. 
 
3.5 
Endpoints 
3.5.1 
Primary Endpoint 
Tolvaptan exposure (Cmax and AUC24h on Day 1 of the treatment period) 
3.5.2 
Secondary Endpoints 
• Pharmacokinetics 
Plasma concentrations and pharmacokinetic parameters of OPC-61815, tolvaptan, 
DM-4103, and DM-4107 
• Pharmacodynamics 
Serum concentrations of sodium and potassium, serum osmolality, biomarkers 
(plasma concentrations of arginine vasopressin and brain natriuretic peptide, plasma 
renin activity, and serum concentrations of N-terminal pro-brain natriuretic peptide 
[NT-proBNP] and troponin), daily urine volume, daily fluid intake, daily fluid 
balance, daily urine sodium excretion, daily urine potassium excretion, and urine 
osmolality 
• Efficacy 
Body weight, congestive symptoms (lower limb edema, other edema, jugular venous 
distension, pulmonary congestion confirmed by chest X-ray, pulmonary rales, third 
cardiac sound, and hepatomegaly), cardiothoracic ratio, and New York Heart 
Association (NYHA) classification 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
41 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.5.3 
Safety Endpoints 
AE reporting, clinical laboratory tests (including pregnancy test), physical examination, 
vital signs (blood pressure, pulse rate, and body temperature), and 12-lead 
electrocardiogram (ECG) 
3.5.4 
Rationale for Endpoints 
Table 3.5.4-1 summarizes the rationale for the endpoints 
Table 3.5.4-1 
Rationale for Endpoints 
Endpoints 
Rationale 
Primary Endpoint 
This is necessary to determine the dose of OPC-61815 that achieves 
tolvaptan exposure equivalent to tolvaptan 15-mg tablet in patients with 
heart failure. Tolvaptan does not accumulate and repeated administration 
of the drug is thought to demonstrate a blood concentration-time profile 
similar to that after single administration. Tolvaptan exposure is measured 
after administration on Day 1 to avoid dropouts. 
Secondary Endpoints 
Efficacy Endpoints 
This is a generic index of systemic fluid retention and used for evaluation 
of diuretic effects. It is considered appropriate for efficacy evaluation of 
OPC-61815 in CHF patients compared with tolvaptan tablets (control). 
 
Body weight 
 
Congestive symptoms 
These symptoms indicate the presence of fluid retention due to CHF. They 
are used for efficacy evaluation of OPC-61815 compared with tolvaptan 
tablets (control). 
 
NYHA Classification 
This index evaluates the severity of heart failure based on subjective 
symptoms. It is considered necessary for evaluating the efficacy of OPC-
61815 compared with tolvaptan tablets (control). 
Pharmacokinetic Endpoints 
To evaluate the pharmacokinetics of the unchanged drug, tolvaptan (active 
metabolite), and other main metabolites following the administration of 
OPC-61815 in patients with heart failure. 
Pharmacodynamic 
Endpoints 
Daily urine volume is a measure of the pharmacodynamic effect (aquaretic 
effect) of tolvaptan and is used for pharmacodynamic evaluation of OPC-
61815 compared with tolvaptan 15-mg tablet (control). Daily fluid intake, 
daily fluid balance (fluid intake - urine volume), urine osmolality, and 
serum osmolality are selected for evaluation of the diuretic effect of OPC-
61815. Urine electrolyte (sodium and potassium) excretion and serum 
electrolyte concentrations (sodium and potassium) are selected to 
investigate the effects of tolvaptan on electrolytes (sodium and potassium). 
Plasma AVP concentration is used to investigate the antagonistic action of 
OPC-61815 against AVP. Other pharmacodynamic endpoints are for 
monitoring of subjects and evaluating the safety of OPC-61815 compared 
with tolvaptan tablets (control). 
Safety Endpoints 
Common safety endpoints are selected for safety evaluation of OPC-61815 
compared with tolvaptan tablets (control). 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
42 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.6 
Measures to Minimize/Avoid Bias 
3.6.1 
Randomization 
Subjects who meet the criteria for enrollment in the treatment period are randomized by 
the Interactive Web Response System (IWRS) to OPC-61815 injection 2 mg group, 
OPC-61815 injection 4 mg group, OPC-61815 injection 8 mg group, OPC-61815 
injection 16 mg group, and tolvaptan 15-mg tablet group at a ratio of 1:1:1:1:1. 
Allocation of subjects to treatments will be documented in a separate allocation record. 
The date of randomization and the assigned number will be documented in the CRF. 
3.6.2 
Blinding 
The vials of lyophilized OPC-61815 injection and placebo injection appear alike, but the 
prepared solutions will look different. (Foaming may remain immediately after 
preparation but will disappear shortly thereafter.) To maintain blinding of all trial site 
staff participating in assessment during the trial, the trial site will appoint one person 
(non-blinded staff) as a person responsible for IMP preparation to prepare all the IMP. 
The person responsible for IMP preparation (non-blinded staff) must be qualified for 
dispensing prepared drugs and appointed at trial site. The person responsible for IMP 
preparation (non-blinded staff) will also prepare tolvaptan and placebo tablets. The 
procedure for preparing the IMP and the procedure for maintaining blinding at the trial 
site by appointing the person responsible for IMP preparation (non-blinded staff) will be 
specified separately in writing. The person responsible for IMP preparation (non-blinded 
staff) will be obliged to keep confidential all information acquired through IMP 
preparation. Any queries related to the IMP are to be addressed to the contact person 
specified in the procedure rather than the trial monitor. 
To maintain access to the IMP throughout the trial, the trial site may appoint a deputy 
person responsible for IMP preparation (non-blinded staff). 
3.7 
Trial Procedures 
Table 3.7-1 summarizes the scheduled observations/tests and assessments. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
43 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Table 3.7-1 
Schedule of Observations/Tests and Assessments 
 
●, Mandatory (before breakfast and IMP administration [before breakfast on the day on which IMP 
administration is not scheduled]); ■, Mandatory (at the specified time point) 
○, Optional (only applicable to the trial sites that have agreed to collect samples for DNA storage in 
advance. Samples for DNA storage will only be collected from subjects who have given written 
consent to DNA storage.) 
aSubject enrollment/randomization:  
Subjects are registered and randomized at screening and on Day 1, respectively, in the IWRS. Only 
the subjects who meet all the inclusion criteria (including the criteria specified in “Table 3.4.3-1 
Criteria for Enrollment in the Treatment Period (Inclusion Criteria of Run-in Period)”) and do not fall 
under any of the exclusion criteria are assigned to IMP administration. Randomization normally takes 
place on Day 1 (or Day -1 if justified. Each subject’s fulfillment of inclusion criterion 8 will be 
verified on Day 1). Completion of the initial administration (Day 1), completion of blood sampling 
Follow-up
Day−7 to
−4
Day−4
Day−3
Day−2
Day−1
Day1
Day2
Day3
Day4
Day5/
End of
treatment
End-of-trial/At
discontinuation
(day after final
administration)
Day12 to 15/
7 to 10 days
after final
administration
Informed consent
■
Consent for DNA storage
(optional)
Subject demographics
■
Inclusion/Exclusion criteria
■
●
Confirmation of use of
concomitant medications/
therapies
Subject registration,
randomizationa
■
●■
●
●
Hospitalization
IMP administration
■
■
■
■
■
Treatment compliance
Use of diuretics (dose fixed)
■
■
■
■
■
■
■
■
■
Plasma drug concentration
(See Table 3.7-2)
●■
●
●
●
●
●
Pharmacodynamics
Serum sodium and potassium
concentrationsb
■
●■
●
●
●
●
●
■
Serum osmolality, biomarkersc
●
●
Daily urine volume, daily fluid
intake, urine sodium/potassium
concentrations, urine osmolality
Efficacy
Body weight
■
●
●
●
●
●
●
●
●
●
■
Congestive symptomsg
■
■
■
■
■
■
■
■
■
■
■
Chest X-rayh
■
■
NYHA Classification
■
Safety
AEs
Clinical laboratory test
■
●
●
■
Physical examination
■
■
■
■
■
■
■
■
■
■
■
Vital signsd
■
●
●
●
●
●
●
●
●
●
■
12-Lead ECGe
■
■
■
Pregnancy testf
■
■
Pharmacogenomics
DNA Storagei
○
Treatment Period
○
■j
■j
■j
                                   Time Point
    Item
Screening
Run-in Period


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
44 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
for plasma drug concentration measurement up to 24 hours after start of IMP administration on Day 1 
(Day 2), and trial completion/discontinuation (end-of-trial/withdrawal) will be recorded in the IWRS. 
bTiming of blood sampling on Day 1 for measurement of serum sodium/potassium concentration: 
Before IMP administration (before breakfast), between 4 and 6 hours after start of IMP administration, 
and between 8 and 12 hours after start of IMP administration. Measurement of serum sodium 
concentration during the treatment period takes place at the trial site in addition to at the central 
laboratory. 
cBiomarkers:  
Plasma AVP concentration, plasma BNP concentration, plasma renin activity, serum NT-proBNP 
concentration, serum troponin concentration will be measured. 
dVital signs: Blood pressure, pulse rate, and body temperature will be measured. 
e12-lead ECG: Between 1 and 2 hours after start of IMP administration on Day 1 and Day 3. 
Subsequently when possible. 
fPregnancy test: Applicable to only female subjects of childbearing potential. 
gCongestive symptoms: Lower limb edema, other edema, jugular venous distension, pulmonary rales, 
third cardiac sound, hepatomegaly will be assessed. 
hChest X-ray: Cardiothoracic ratio and pulmonary congestion will be assessed. 
If the subject underwent chest X-ray at examination before participation in the trial, cardiothoracic 
ratio and pulmonary congestion may be assessed using the radiograph (must be taken within 14 days 
before consent) instead of obtaining a new one at the screening examination. 
iDNA storage: Blood will be collected before IMP administration on Day 1. 
If blood cannot be collected at the above time point, collection may take place at any subsequent time 
point during the trial. 
j12-lead ECG, chest X-ray, and assessment for NYHA classification will each be conducted once during 
the run-in period. 
 
Table 3.7-2 
Blood Sampling Schedule for Plasma Drug Concentration 
Measurement 
Sampling Time Point 
Time Window 
Day 1 
Before start of IMP administration 
From 2 hours to immediately before 
start of IMP administration 
 
1 hour after start of IMP administration 
Within 5 minutes after end of 
administration 
 
1.5 hours after start of IMP administration 
Specified time point ± 5 minutes 
 
2 hours after start of IMP administration 
Specified time point ± 5 minutes 
 
4 hours after start of IMP administration 
Specified time point ± 20 minutes 
 
6 hours after start of IMP administration 
Specified time point ± 30 minutes 
 
12 hours after start of IMP administration 
Specified time point ± 1 hour 
Day 2 
24 hours after start of administration on Day 1 (and 
before administration on Day 2) 
22 to 24 hours after start of 
administration on Day 1 
Day 3 
24 hours after start of administration on Day 2 (and 
before administration on Day 3) 
22 to 24 hours after start of 
administration on Day 2 
Day 4 
24 hours after start of administration on Day 3 (and 
before administration on Day 4) 
22 to 24 hours after start of 
administration on Day 3 
Day 5 
24 hours after start of administration on Day 4 (and 
before administration on Day 5) 
22 to 24 hours after start of 
administration on Day 4 
Day 6 
24 hours after start of administration on Day 5 
22 to 24 hours after start of 
administration on Day 5 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
45 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
 
3.7.1 
Schedule of Assessments 
3.7.1.1 
Screening 
After obtaining informed consent, the investigator or subinvestigator will assign a subject 
identifier to each subject according to Section 3.3.2 Subject Selection and Numbering. 
The date of consent and subject identifier will be recorded in source documents and CRF. 
The subject will then be registered in the IWRS. The IWRS will be used to monitor 
subject registration, etc. The use of the system will be described in a separate procedure. 
After acquisition of informed consent, subjects will undergo the following screening 
(examinations/tests) between 7 days and 4 days before administration (Day −7 to Day −4) 
for eligibility assessment. The result of eligibility assessment will be recorded in source 
documents and CRF. 
[Tests/Examinations] 
Subject demographics [birth date, sex, height, nationality, race, ethnicity, underlying 
disease, heart failure subtype, presence/absence and type of arrhythmia, presence/absence 
of pacemaker, presence/absence of ICD, complications, and medical history], serum 
sodium concentration, serum potassium concentration, clinical laboratory tests, physical 
examination, vital signs (blood pressure, pulse rate, and body temperature), body weight, 
congestive symptoms, chest X-rayNote (cardiothoracic ratio and pulmonary congestion), 
confirmation of use of concomitant medications and therapies, urine pregnancy test (only 
in female subjects of childbearing potential) 
Note) If the subject underwent chest X-ray at examination before participation in the trial, 
cardiothoracic ratio and pulmonary congestion may be assessed using the radiograph 
(must be taken within 14 days before consent) instead of obtaining a new one at the 
screening examination. 
3.7.1.2 
Run-in Period (Day −3, Day −2, and Day −1) 
The investigator or subinvestigator will perform the tests and examinations specified 
below to decide whether the subject is eligible for enrollment in the treatment period. The 
dose and regimen of the diuretics the subject is using at the start of the run-in period (on 
Day −3) will not be modified until the end-of-trial examination (or withdrawal 
examination), irrespective of prior use of diuretics and its administration methods before 
the run-in period. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
46 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
The subject will be hospitalized from the day before the run-in period to the end-of-trial 
(or discontinuation) examination. 
(1) Each Day during Run-in Period (3 Days) 
(a) Before breakfast 
• Vital signs 
• Body weight 
(b) After breakfast 
The subject will be asked to void his/her bladder immediately before breakfast to start 
pooling of urine and measurement of fluid intake for the following measurements: 
• Daily urine volume 
• Daily fluid intake 
• Daily fluid balance (difference between daily fluid intake and daily urine volume) 
• Daily urine sodium excretion and daily urine potassium excretion (calculated 
using urine sodium concentration, urine potassium concentration, and daily urine 
volume) 
• Urine osmolality 
(c) Administration of diuretics 
(d) At an appropriate time point of the scheduled day 
• Physical examination 
• Congestive symptoms 
• Confirmation of use of concomitant drugs and therapies 
• AEs 
(2) On 1 Day during the Run-in Period (3 Days) 
Each will be performed/assessed once, when appropriate. 
• 12-lead ECG 
• Chest X-ray 
• NYHA Classification 
 
3.7.1.3 
Randomization and Initiation of Treatment Period 
(1) Assessment of Eligible for Enrollment in the Treatment Period 
Whether or not the subject fulfills the criteria presented in Table 3.4.3-1 Criteria for 
Enrollment in the Treatment Period (Inclusion Criteria of Run-in Period) is decided based 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
47 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
on the use of diuretics, body weight, and congestive symptoms during the run-in period. 
The decision is entered into the IWRS. 
(2) Assignment of Subjects to Treatments 
The subject who fulfills the criteria for enrollment in the treatment period will be 
randomized to one of the 5 groups listed below for IMP administration in a double-blind 
manner. The investigator or subinvestigator will verify the drug number assigned on the 
IWRS. 
• OPC-61815 injection 2 mg group 
• OPC-61815 injection 4 mg group 
• OPC-61815 injection 8 mg group 
• OPC-61815 injection 16 mg group 
• Tolvaptan 15-mg tablet group 
 
3.7.1.4 
Treatment Period (Day 1) 
(1) Before IMP Administration (Before Breakfast) 
• Plasma drug concentration (within 2 hours before IMP administration) 
• Serum sodium concentration, serum potassium concentration, serum osmolality, 
and biomarkers 
• Clinical laboratory tests and vital signs 
• Body weight 
• Blood sampling for DNA storage (The subject may or may not agree to DNA 
storage. The subject’s consent to DNA storage will be obtained before blood 
sampling.) 
(2) After Tests/Blood Sampling and After Breakfast 
The subject will be asked to void his/her bladder immediately after breakfast to start 
pooling of urine and measurement of fluid intake for the following measurements: 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine sodium excretion and daily urine potassium excretion 
• Urine osmolality 
(3) IMP Administration 
The investigator or subinvestigator will administer the IMP to the subject after verifying 
that the subject meets the inclusion criteria and does not fall under any of the exclusion 
criteria. The investigator or subinvestigator subsequently will record IMP administration 
in the IWRS. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
48 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
(4) Administration of Diuretics 
(5) Tests and Assessments 
The investigator or subinvestigator will perform the tests described below. 
Table 3.7.1.4-1 
Tests on Day 1, Their Scheduled Time Points, and Blood 
Sampling Time Points After IMP Administration 
Item 
Time Point 
Time Window 
Plasma drug concentration 
1 hour after start of IMP 
administration 
Within 5 minutes after end 
of IMP administration 
 
1.5 hours after start of IMP 
administration 
Specified time point ± 5 
minutes 
 
2 hours after start of IMP 
administration 
Specified time point ± 5 
minutes 
 
4 hours after start of IMP 
administration 
Specified time point ± 20 
minutes 
 
6 hours after start of IMP 
administration 
Specified time point ± 30 
minutes 
 
12 hours after start of IMP 
administration 
Specified time point ± 1 hour 
Serum sodium concentration, 
serum potassium concentration 
4 to 6 hours after start of IMP 
administration 
 
 
8 to 12 hours after start of IMP 
administration 
 
12-lead ECG 
1 to 2 hours after start of IMP 
administration 
 
Physical examination 
When appropriate on Day 1 
 
Congestive symptoms 
When appropriate on Day 1 
 
Confirmation of use of 
concomitant drugs and therapies 
When appropriate on Day 1 
 
Treatment compliance 
When appropriate on Day 1 
 
AEs 
When appropriate on Day 1 
 
 
3.7.1.5 
Treatment Period (Day 2) 
(1) Before IMP Administration (Before Breakfast) 
• Plasma drug concentration (24 hours after start of IMP administration on Day 1) 
• Serum sodium concentration and serum potassium concentration 
• Vital signs 
• Body weight 
(2) After Tests/Blood Sampling and After Breakfast 
The subject will be asked to void his/her bladder immediately after breakfast to start 
pooling of urine and measurement of fluid intake for the following measurements: 
• Daily urine volume, daily fluid intake, and daily fluid balance 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
49 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
• Daily urine sodium excretion and daily urine potassium excretion 
• Urine osmolality 
(3) IMP Administration 
(4) Administration of Diuretics 
(5) When Appropriate on Day 2 
• Physical examination 
• Congestive symptoms 
• Confirmation of use of concomitant drugs and therapies 
• Treatment compliance 
• AEs 
 
3.7.1.6 
Treatment Period (Day 3) 
(1) Before IMP Administration (Before Breakfast) 
• Plasma drug concentration (24 hours after start of IMP administration on Day 2) 
• Serum sodium concentration and serum potassium concentration 
• Vital signs 
• Body weight 
(2) After Tests/Blood Sampling and After Breakfast 
The subject will be asked to void his/her bladder immediately after breakfast to start 
pooling of urine and measurement of fluid intake for the following measurements: 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine sodium excretion and daily urine potassium excretion 
• Urine osmolality 
(3) IMP Administration 
(4) Administration of Diuretics 
(5) One to 2 Hours after IMP Administration 
• 12-lead ECG 
(6) When Appropriate on Day 3 
• Physical examination 
• Congestive symptoms 
• Concomitant drugs and therapies 
• Treatment compliance 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
50 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
• AEs 
 
3.7.1.7 
Treatment Period (Day 4 and Day 5) 
(1) Before IMP Administration (Before Breakfast) 
• Plasma drug concentration (24 hours after start of IMP administration on Day 3 
and Day 4) 
• Serum sodium concentration and serum potassium concentration 
• Vital signs 
• Body weight 
(2) After Tests/Blood Sampling and After Breakfast 
The subject will be asked to void his/her bladder immediately after breakfast to start 
pooling of urine and measurement of fluid intake for the following measurements: 
• Daily urine volume, daily fluid intake, and daily fluid balance 
• Daily urine sodium excretion and daily urine potassium excretion 
• Urine osmolality 
(3) IMP Administration 
(4) Administration of Diuretics 
(5) Each Day, When Appropriate 
• Physical examination 
• Congestive symptoms 
• Concomitant drugs and therapies 
• Treatment compliance 
• AEs 
 
3.7.1.8 
Treatment Period (End-of-trial or at Discontinuation) 
When the subject completes trial treatment on Day 5, he/she will undergo the tests and 
assessments specified below as the end-of-trial examination on Day 6. If the subject 
discontinues trial treatment prematurely before the duration of administration reaches 5 
days (see Section 3.8.3.1 Treatment Discontinuation), he/she will be requested to undergo 
the same tests and assessments the day after the final IMP administration, if possible. 
Completion of the end-of-trial or withdrawal examination will be recorded in the IWRS. 
(1) Before Breakfast 
• Plasma drug concentration (24 hours after start of IMP administration on Day 5) 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
51 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
• Serum sodium concentration, serum potassium concentration, serum osmolality, 
and biomarkers 
• Clinical laboratory tests and vital signs 
• Body weight 
(2) Administration of Diuretics 
(3) When Appropriate on the Day after Final Administration 
• Physical examination 
• 12-lead ECG 
• Congestive symptoms 
• Chest X-ray 
• NYHA Classification 
• Confirmation of use of concomitant drugs and therapies 
• AEs 
 
3.7.1.9 
Post-treatment Follow-up Period (7 to 10 days after final 
administration) 
The investigator or subinvestigator will perform the following tests or examinations 
between 7 and 10 days after final IMP administration. The tests/examinations may be 
performed on an outpatient basis if the subject has been discharged. 
• Serum sodium concentration and serum potassium concentration 
• Clinical laboratory tests, physical examination, and vital signs 
• Body weight and congestive symptoms 
• Urine pregnancy test (only in female subjects of childbearing potential) 
• Confirmation of use of concomitant drugs and therapies 
• AEs 
 
3.7.1.10 
Follow-up 
If an AE has not resolved by the end-of-trial examination or the time of discontinuation, 
the event will be followed as described in Section 5.7 Follow-up of Adverse Events After 
Treatment Period. 
3.7.2 
Prior and Concomitant Medication 
The investigator or subinvestigator will document in the CRF all the drugs and therapies 
given to the subject between the day of signing informed consent and end-of-
trial/withdrawal examination. The investigator or subinvestigator will also document in 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
52 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
the CRF the drugs and therapies given for the treatment of AEs by the last scheduled 
contact or the drugs/therapies that caused AEs. 
3.7.3 
Efficacy Assessments 
3.7.3.1 
Body Weight 
The investigator or subinvestigator will have the subject void his/her bladder at least once 
after awakening and subsequently weigh the subject on an appropriately calibrated scale 
before breakfast after taking precautions to minimize the effect of defecation and clothing. 
The date and time of measurement and the weight (read to 1 decimal place in kilograms) 
will be recorded in the source documents and CRF. If the scale used measures to 2 or 
more decimal places, the reading is rounded to 1 decimal place and recorded. 
3.7.3.2 
Congestive Symptoms (Lower Limb Edema, Other Edema, 
Jugular Venous Distension, Pulmonary Rales, Third Cardiac 
Sound, and Hepatomegaly) 
The investigator or subinvestigator will examine the subject for congestive symptoms 
(lower limb edema, other edema, jugular venous distension, hepatomegaly, pulmonary 
rales, and third cardiac sound) and decides whether the subject has the symptoms and 
assesses the severity of each symptom in the manner described below. The investigator or 
subinvestigator will document the date of assessment together with the results of 
assessment in the source documents and CRF. 
(1) Lower Limb Edema 
The severity of edema in the subject’s tibial border or dorsum of the foot will be assessed 
in the sitting position using the scale below. 
Table 3.7.3.2-1 
Scale for Lower Limb Edema 
 
Severity 
Description 
0 
Absent 
No indentation 
1 
Mild 
Slight indentation 
2 
Moderate 
Deep indentation 
3 
Severe 
Visible edema 
 
(2) Other Edema 
The same scale to be used in assessment of lower limb edema will be used. The same 
area will be used for assessment both before and after IMP administration. The area of 
assessment will be recorded in the source documents and CRF. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
53 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
(3) Jugular Venous Distension 
Whether or not the subject has jugular venous distension will be documented, together 
with the vertical height (in centimeters, to 1 decimal place) from the sternal angle to the 
highest point of pulsation of the internal jugular vein if distension is observed. 
(4) Pulmonary Rales 
Whether pulmonary rales are heard on auscultation will be documented. 
(5) Third Cardiac Sound 
Whether third cardiac sound is heard on auscultation will be documented. 
(6) Hepatomegaly 
Whether or not the liver is palpable will be documented, together with the palpated width 
(distance from the costal arch on the right nipple line, to 1 decimal place in centimeters) 
if palpable. 
3.7.3.3 
Chest X-ray (Cardiothoracic Ratio and Pulmonary Congestion) 
The investigator or subinvestigator will perform chest X-ray and document the date in the 
source documents and CRF. The cardiothoracic ratio and pulmonary congestion will be 
assessed as described below. 
(1) Cardiothoracic Ratio 
The investigator or subinvestigator will calculate the cardiothoracic ratio to 2 decimal 
places or lower if possible, rounds the value to 1 decimal place, and document the value 
to 1 decimal place in source documents and CRF. 
(2) Pulmonary Congestion 
The investigator or subinvestigator will assess the severity of pulmonary congestion 
using the scale below and document the assessment in the source documents and CRF. 
Table 3.7.3.3-1 
Scale of Pulmonary Congestion 
 
Severity 
Description 
0 
Absent 
No congestion 
1 
Mild 
Pulmonary vein congestion 
2 
Moderate 
Interstitial lung edema 
3 
Severe 
Pulmonary alveolar edema 
Source: Forrester JS, et.al.,9 with modification 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
54 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.7.3.4 
NYHA Classification 
The investigator or subinvestigator will classify the extent of heart failure in the subject 
using the NYHA classification system.10 The investigator or subinvestigator will 
document the date of assessment together with the results of assessment in the source 
documents and CRF. 
Table 3.7.3.4-1 
NYHA Classification 
Functional capacity 
Class I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitations, dyspnea, and/or angina. 
Class II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results 
in fatigue, palpitations, dyspnea, and/or angina. 
Class III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity 
causes fatigue, palpitations, dyspnea, and/or angina. 
Class IV 
Unable to carry out any physical activity without discomfort. Symptoms of fatigue, 
palpitations, or dyspnea are present at rest. If any physical activity is undertaken, 
discomfort increases. 
 
3.7.4 
Safety Assessments 
3.7.4.1 
Adverse Events 
Refer to Section 5, Reporting of Adverse Events. 
3.7.4.2 
Clinical Laboratory Assessments 
The patient will undergo venous blood withdrawal and urine collection for the clinical 
laboratory tests specified in Table 3.7.4.2-1 at specified time points. The date and time of 
blood sampling and the date of urine collection will be recorded in source documents. 
The samples will be sent to the contract laboratory for central testing. 
To ensure subject safety and to facilitate close monitoring of serum sodium concentration 
by the investigator or subinvestigator, serum sodium concentration will be determined at 
the trial site during the treatment period separately from the measurement at the contract 
laboratory. Whether blood for measurement of serum sodium concentration is collected 
and, if collected, the date and time of blood sampling and the result of measurement will 
be recorded in the source documents and CRF. 
The contract laboratory will perform the measurements for the parameters listed in the 
table below according to their established procedure and report the results to the sponsor 
and the investigator or subinvestigator. Whether blood and urine have been collected as 
well as the date and time of blood sampling and the date of urine collection (if collected) 
will be recorded in the CRF. The electronic file documenting the test results will be 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
55 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
delivered from the contract laboratory to the sponsor and kept as source data. 
Transcription of the results into the CRF is unnecessary. 
Table 3.7.4.2-1 
Clinical Laboratory Assessments 
Hematology: 
Red Blood Cell count 
Hemoglobin 
Hematocrit 
White Blood Cell count with differential 
(neutrophil, eosinophil, basophil, monocyte, 
lymphocyte) 
Platelet count 
Serum Chemistry: 
Protein, total 
Albumin 
Bilirubin, total 
AST (GOT) 
ALT (GPT) 
Alkaline phosphatase (ALP) 
γ-Glutamyl transferase (γ-GTP) 
Lactic dehydrogenase (LDH) 
Creatine kinase (CK [CPK]) 
Blood glucose 
Cholesterol, total 
Triglyceride 
Urea nitrogen 
Creatinine 
Uric acid 
Serum electrolytes (sodium, potassium, chloride, 
calcium) 
PAP, TRACP-5bb 
Urinalysis (qualitative): 
pH 
Protein 
Glucose 
Blood 
Ketone body 
Bilirubin 
Urobilinogen 
Additional Tests: 
Pregnancy test (hCG test)a in WOCBP 
aUrine pregnancy test will be performed at screening and follow-up. If a female subject has a positive 
urine pregnancy test, she will undergo a serum pregnancy test according to Section 5.5 Pregnancy. 
bProstatic acid phosphatase (PAP) and tartrate-resistant acid phosphatase (TRACP-5b): Only on Day 1 
 
A pregnancy test will be conducted in women of childbearing potential (WOCBP) at the 
screening examination; the test result must be available prior to IMP administration. A 
pregnancy diagnosis support reagent provided by the sponsor will be used to perform the 
urine human chorionic gonadotropin (hCG) test. The test will be repeated if the result is 
inconclusive. The investigator or subinvestigator will review the test result and record 
whether or not the test is performed together with the test date and result (positive or 
negative) if performed in source documents and CRF. 
3.7.4.3 
Physical Examination and Vital Signs (Blood Pressure, Pulse 
Rate, and Body Temperature) 
(1) Physical Examination 
The subject will undergo a physical examination at specified time points. In the physical 
examination, the head, ears, eyes, nose and pharynx, chest, abdomen, urogenital organs, 
limbs, nerve, and skin and mucous membrane will be examined. The investigator or 
subinvestigator will bear the primary responsibility for assessment based on the physical 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
56 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
examination. Wherever possible, the physical examination of a subject will be performed 
by the same doctor. 
The date of each physical examination and the findings will be recorded in source 
documents and CRF. 
If, based on the physical examination, there is a new (ie, not present at baseline) clinically 
significant finding after IMP administration, the finding will be recorded as an AE and 
followed until its outcome has been sufficiently evaluated. 
(2) Blood Pressure and Pulse Rate 
Blood pressure (both diastolic and systolic) and pulse rate will be measured in the supine 
position using a well-maintained instrument after the subject has rested for at least 3 
minutes. Whether or not the measurement has been performed, together with the date and 
time of measurement and the blood pressure and pulse rate measurements will be 
recorded in source documents and CRF. 
(3) Body Temperature 
Axillary temperature will be measured to 1 decimal place in Celsius using a well-
maintained thermometer. Whether or not the measurement has been performed, together 
with the date and time of measurement and the measured temperature will be recorded in 
source documents and CRF. When the thermometer used measures to 2 or more decimal 
places, the reading is rounded to 1 decimal place and documented. 
3.7.4.4 
12-lead Electrocardiogram 
The 12-lead electrocardiograph sent from the central ECG analysis laboratory will be 
used to obtain resting 12-lead ECG according to the method specified by the central ECG 
analysis laboratory. The investigator or subinvestigator assesses whether the ECG finding 
is normal or abnormal. He/she then will record whether or not the ECG is performed in 
source documents and CRF, together with the date of ECG and normal/abnormal 
assessment (including a description of any abnormal finding) if performed. 
The ECG is sent to the central ECG analysis laboratory for calculation of heart rate, PR 
interval, RR interval, QRS interval, QT interval, and QTc intervals (QTcB and QTcF). 
The central ECG analysis laboratory will deliver the 12-lead ECG analysis report to the 
investigator or subinvestigator. 
The investigator or subinvestigator will then review their ECG assessment with reference 
to the analysis report and signs and files the report. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
57 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
The 12-lead ECG analysis report (in electronic format) sent from the central ECG 
analysis laboratory to the sponsor constitutes source data. Transcription of the heart rate, 
PR interval, RR interval, QRS interval, QT interval, and QTc intervals (QTcB and QTcF) 
to the CRF is unnecessary. 
3.7.5 
Pharmacokinetic/pharmacodynamic/pharmacogenomic 
Assessments 
3.7.5.1 
Pharmacokinetic Assessments 
3.7.5.1.1 
Pharmacokinetic Blood Samples 
(1) Blood Sampling Schedule 
• Day 1 of treatment period: Before IMP administration and 1, 1.5, 2, 4, 6, 12, and 24 
hours after start of IMP administration 
• Day 3 of treatment period: 24 hours after start of IMP administration on Day 2 (and 
before administration on Day 3) 
• Day 4 of treatment period: 24 hours after start of IMP administration on Day 3 (and 
before administration on Day 4) 
• Day 5 of treatment period: 24 hours after start of IMP administration on Day 4 (and 
before administration on Day 5) 
• Day 6 of treatment period: 24 hours after start of IMP administration on Day 5 
See Table 3.7-2 for the time windows for individual sampling points. 
(2) Blood Sampling and Test Method 
The contract laboratory will collect blood samples and send them to the bioanalytical 
laboratory. Detailed sample handling and shipping instructions are provided in Appendix 
1. 
The bioanalytical laboratory will determine plasma concentrations of OPC-61815 free 
form, tolvaptan, DM-4103, and DM-4107. The bioanalytical laboratory will report the 
test results to the sponsor while maintaining blinding. After unblinding, they will submit 
bioanalytical data in electronic format to the sponsor. 
Whether or not blood is collected, type of blood collected (venous or arterial), and date 
and time of blood sampling will be recorded in the CRF. Transcription of the test results 
(reported directly from the bioanalytical laboratory to the sponsor) to the CRF is 
unnecessary. 
When new information related to the IMP becomes available, analysis of a metabolite not 
specified in the protocol may additionally be performed. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
58 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
(3) Rationale for Blood Sampling Schedule 
This trial will investigate the dose of OPC-61815 that achieves tolvaptan exposure similar 
to tolvaptan 15-mg tablet in patients with heart failure. At the same time, plasma drug 
concentration data will be collected for evaluation of the pharmacokinetics following 
multiple OPC-61815 administration in patients with heart failure. For Day 1 of the 
treatment period, a blood will be collected predose, at the simulated tmax of OPC-61815 
(1 hour after the start of administration), 3 time points around the tmax of tolvaptan (1, 1.5, 
and 2 hours after the start of administration), 3 time points in the estimated elimination 
phase of OPC-61815 (2, 4, and 6 hours after the start of administration), 3 time points in 
the estimated elimination phase of tolvaptan (6, 12, and 24 hours after the start of 
administration). These have been selected to calculate relevant pharmacokinetic 
parameters of OPC-61815 and tolvaptan based on the simulation of 1-hour intravenous 
administration using a population pharmacokinetic model based on data from 3 trials (the 
single intravenous dose trial of OPC-61815 in healthy adults [263-08-001], repeated 
intravenous dose trial of OPC-61815 in healthy adults [263-09-001], and trial 
investigating the rate of intravenous OPC-61815 administration in healthy adults [263-
10-005]) and considering feasibility referring clinical pharmacology trial in Japanese 
patients with heart failure (156-06-004). One sampling time point (24 hours after the start 
of administration) for each of Day 2, Day 3, Day 4, and Day 5 of the treatment period is 
selected to confirm steady-state has been reached. A total of 12 blood sampling time 
points will be selected. 
3.7.5.2 
Pharmacodynamic Assessments 
3.7.5.2.1 
Clinical Laboratory Tests for Pharmacodynamic Analysis 
(Serum Sodium Concentration, Serum Potassium 
Concentration, Serum Osmolality, Biomarkers, Daily Urine 
Sodium Excretion, Daily Urine Potassium Excretion, and 
Urine Osmolality) 
Samples for the parameters specified in Table 3.7.5.2.1-1 will be collected according to 
the schedule shown in Section 3.7.1 Schedule of Assessments. The date and time of 
sampling of venous blood will be recorded in source documents and CRF. Serum sodium 
and potassium concentrations will be obtained using the data generated in clinical 
laboratory tests conducted at the same sampling time points discussed in Section 3.7.4.2 
Clinical Laboratory Assessments. The sampling, processing, and storage procedure are 
provided in Appendix 1. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
59 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Table 3.7.5.2.1-1 
Pharmacodynamic Laboratory Tests 
Serum: 
Serum sodium concentration 
Serum potassium concentration 
Serum osmolality 
Serum troponin-I concentration 
Serum NT-proBNP concentration 
Plasma: 
Plasma AVP concentration 
Plasma BNP concentration 
Plasma Renin Activity 
Urine: 
Urine sodium concentration 
Urine potassium concentration 
Urine osmolality 
 
All samples will be sent to the contract laboratory. The contract laboratory will perform 
testing on all the samples according to their established procedure and report the results 
to the sponsor and investigator or subinvestigator. The test results reported from the 
contract laboratory to the sponsor in electronic format will constitute the source data. 
Transcription of results to the CRF is unnecessary. 
To ensure subject safety and to facilitate close monitoring of serum sodium concentration 
by the investigator or subinvestigator, serum sodium concentration will be determined at 
the trial site during the treatment period separately from the measurement at the contract 
laboratory. Whether blood for measurement of serum sodium concentration is collected 
and, if collected, the date and time of blood sampling and the result of measurement will 
be recorded in source documents and CRF. 
Daily urine sodium excretion and daily urine potassium excretion are calculated by 
multiplying urine sodium concentration and urine potassium concentration, respectively, 
by daily urine volume. Urine excretion will be calculated by the sponsor and not need to 
be recorded in the CRF. 
3.7.5.2.2 
Daily Urine Volume 
During the run-in period, urine volume will be measured each day from immediately after 
voiding after breakfast to voiding after breakfast the following day (measurement of the 
last day of the run-in period ends before IMP administration on Day 1 of the treatment 
period). 
During the treatment period (after start of IMP administration on Day 1), urine volume 
will be measured each day from after voiding immediately before administration to after 
voiding immediately before administration the next day (continued until the day after 
final IMP administration). 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
60 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Whether or not urine volume is measured will be recorded in source documents and CRF, 
together with the start and end date and time of each measurement and daily urine 
volume (if measured). 
3.7.5.2.3 
Daily Fluid Intake 
The subject’s fluid intake (including beverages [eg, fruit juice, milk, tea], water, and 
infusion solution) will be measured daily for the same period as urine. Whether or not 
fluid intake is measured will be recorded in source documents and CRF, together with the 
start and end date and time of each measurement and daily fluid intake (if measured). 
Water taken together with IMP will be included as fluid intake during the period that 
starts after administration. 
3.7.5.2.4 
Daily Fluid Balance 
Daily fluid balance is calculated by subtracting daily urine volume from daily fluid intake. 
It will be calculated by the sponsor and not need to be recorded in the CRF. 
3.7.5.3 
Pharmacogenomic Assessments 
3.7.5.3.1 
DNA Storage 
(1) Purpose for Storage 
DNA samples will be stored so that the relationships between interindividual differences 
in the efficacy, safety, or pharmacokinetics of OPC-61815 and variations of DNA 
characteristics can be investigated in the future. 
(2) Target Subjects for Storage 
Sampling for DNA storage will take place only at the trial sites that have agreed to 
perform sampling for DNA storage prior to the trial. DNA samples will be collected only 
from subjects who have given consent to DNA storage in writing. Withdrawing consent 
to participate in the trial does not constitute withdrawal of consent for DNA storage. 
DNA samples will be retained only if the IRB of the trial site grants approval. Consent 
for DNA storage will be obtained before blood sampling for DNA storage. 
(3) Procedure for Storage 
1) Blood sampling schedule 
Blood sampling will be performed on Day 1 (predose). If blood cannot be 
collected on Day 1 (predose), blood sampling may again take place at any 
subsequent time point during the trial. Whether or not a blood sample for DNA 
storage is collected will be recorded in source documents and CRF, together with 
the date of collection (if collected). 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
61 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
2) Blood sampling procedure 
Two milliliters of blood (venous or arterial, either is acceptable) will be collected 
by venous puncture or via an indwelling catheter into a plastic collection tube 
(containing ethylenediaminetetraacetic acid [EDTA]). After inverting to mix the 
content, the tube will be frozen. 
3) Sample shipment 
The trial site will include the protocol number, subject number, and date of blood 
sampling on the label of the blood sample for DNA storage. The contract 
laboratory will keep the sample frozen and send it to the DNA storage facility. 
4) DNA isolation and storage 
At the DNA storage facility, the personal information manager will assign a new 
personal code to each sample to make it double-coded, followed by isolation and 
freezing of DNA. 
5) DNA storage period 
DNA will be stored until (1) genomic/genetic analysis becomes unnecessary, (2) 
clinical development is discontinued, (3) 15 years after consent, or (4) the subject 
withdraws consent for DNA storage, whichever comes earlier. 
6) DNA destruction 
When the sponsor requests destruction of a stored DNA sample, the DNA storage 
facility will destroy it by incineration according to their established procedure. 
 
(4) Genomic/genetic Analysis 
Genomic/genetic analysis will be performed only when investigating the relationships 
between interindividual differences in the efficacy, safety, or pharmacokinetics of OPC-
61815 and variations of DNA characteristics is expected to produce meaningful results. 
When it has been decided to perform the genomic/genetic analysis, a pharmacogenomics 
protocol will be prepared. The analysis will be performed in compliance with GCP. 
Genomic/genetic analysis will analyze genes that may be correlated with interindividual 
differences in the efficacy, safety, or pharmacokinetics of OPC-61815, but no such genes 
have been identified at this point. 
A genome wide association study using DNA chip/microarray/next-generation sequencer 
may also be performed in conjunction with genomic/genetic analysis. Even in such cases, 
the results will never be used for reasons other than identifying the genes correlated with 
interindividual differences in the efficacy, safety, or pharmacokinetics of OPC-61815. 
The genomic/genetic analysis laboratory will report the results of genomic/genetic 
analysis of double-coded samples to the sponsor. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
62 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
If a subject requests to be withdrawn from the trial, the results of genomic/genetic 
analysis obtained from the subject’s DNA sample by the time the request is made will not 
be destroyed. 
(5) Disclosure of the Results of Genomic/genetic Analysis to the Subject 
Genomic/genetic analysis using DNA samples collected in this trial will target genes 
correlated with interindividual differences in the efficacy, safety, or pharmacokinetics of 
OPC-61815. Any correlation discovered in the analysis will only be exploratory or at an 
early stage of research without sufficient scientific reliability in terms of accuracy, 
certainty, and other relevant elements. The sponsor will not disclose the results of 
genomic/genetic analysis to subjects because providing scientifically ambiguous 
information would be of no benefit to subjects. 
(6) Consent for DNA Storage and Withdrawal 
Written information about DNA storage and genomic/genetic analysis will be prepared 
separately from that about the trial. The subject’s signature will be obtained on the ICF 
for DNA storage. If a subject withdraws consent for DNA storage during the storage 
period, the sponsor will request the DNA storage facility to destroy his/her DNA. 
Withdrawing consent to participate in the trial does not constitute withdrawal of consent 
for DNA storage. When the sponsor requests destruction of a subject’s DNA, the DNA 
storage facility will destroy the subject’s DNA sample while keeping the sample 
anonymity. If a subject requests to be withdrawn from the trial, the results of 
genomic/genetic analysis obtained from the subject’s DNA sample by the time the 
request is made will not be destroyed. 
3.7.6 
End of Trial 
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up case report form (CRF) page for the last 
subject completing or withdrawing from the trial. 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.8.1 
Entire Trial or Treatment Arms 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to the heads of trial sites and regulatory authorities in accordance with regulatory 
requirements. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
63 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.8.2 
Individual Site 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB if judged to be necessary for medical, safety, regulatory, ethical or other reasons 
consistent with applicable laws, regulations, and GCP. The head of the trial site will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB at the 
site. 
3.8.3 
Individual Subject Discontinuation 
3.8.3.1 
Treatment Discontinuation 
In the event of any of 1) through 10) below, IMP administration in the subject will be 
stopped followed by the withdrawal examination specified in Section 3.7.1 Schedule of 
Assessments. The investigator or subinvestigator will record the event in detail in source 
documents and CRF together with the date and reason for discontinuation. 
1) Subject’s request for withdrawal 
2) Discovery that the subject does not meet the inclusion criteria (including those for 
enrollment in the treatment period) or falls under any of the exclusion criteria 
after the start of the treatment period 
3) Occurrence of an AE(s) that makes continued IMP administration difficult 
4) A clinical laboratory value (AST or ALT) is obtained that equals or exceeds 3 
times the upper limit of normal (ULN) 
5) It is found that the serum sodium concentration determined at the trial site or 
central laboratory has increased to 12 mEq/L or higher from the predose value 
within 24 hours after the start of IMP administration 
6) It is found that the serum sodium concentration determined at the trial site or 
central laboratory has increased to 155 mEq/L or higher during the treatment 
period 
7) Use of prohibited concomitant drugs 
8) Noncompliance with rule 1) in the restrictions for concomitant drugs 
9) Confirmed or suspected pregnancy after the start of the treatment period 
10) Deviation from the protocol becomes inevitable or the investigator or 
subinvestigator decides that the subject needs to be withdrawn from the trial for 
any other reason 
 
After randomization, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator or 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
64 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
subinvestigator. However, each investigator or subinvestigator must comprehensively 
review the circumstances and offer the subject options for continued treatment to the 
degree possible as described in Section 3.8.3.4. 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation 
A subject may discontinue IMP for a number of reasons including those listed below: 
• Reasons related to AE: 
− Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard 
− Continuing IMP places the subject at undue risk as determined by the investigator 
or subinvestigator (eg, a safety concern that is possibly, probably, or likely related 
to IMP) 
• Serious adverse event (SAE) 
• A clinical laboratory value (AST or ALT) is obtained that equals or exceeds 3 
times the ULN 
• An increase in the serum sodium concentration to 12 mEg/L or higher from 
the predose value within 24 hours after the start of administration 
• An increase in the serum sodium concentration to 155 mEq/L or higher during 
the treatment period 
• Other potentially IMP-related safety concerns or AEs 
• Death 
• Reasons unrelated to medical condition (provide detail and review AE history with 
subject) 
• Withdrawal of informed consent (complete written withdrawal of consent form) 
• Lost to follow-up 
• Pregnancy (see Section 5.5) 
• Termination of all or part of the trial by the sponsor 
 
If the subject discontinues IMP due to an AE, the investigator or subinvestigator, or other 
trial personnel, will make every effort to follow the event until it has resolved or 
stabilized. Follow up procedures in Section 3.8.3.1 must be followed. 
3.8.3.3 
Withdrawal of Consent 
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator or 
subinvestigator can also discontinue a subject’s participation in the trial at any time if 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
65 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
medically necessary. Unless the subject provides their written withdrawal of consent or 
there is other written documentation by the investigator or subinvestigator confirming the 
subject’s verbal intent to completely withdraw from the trial, subjects should be followed 
for all protocol-specified evaluations and assessments, if possible. 
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial ICF): 
• Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit). 
• Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff). 
• Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives. 
• Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician). 
• Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, 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 [interrupt or] discontinue IMP 
administration, which is not equivalent to a complete withdrawal of consent for further 
participation (see Section 3.8.3.1). A subject may, however, indicate that further trial 
participation is creating a burden on their work or social schedule. Therefore, the 
investigator or subinvestigator should follow the procedures outlined in Section 3.8.3.4 to 
determine if the subject can continue participation in the trial if modifications to his/her 
treatment and/or schedule of assessments can be accommodated. Only subjects who 
withdraw their permission for all of the above degrees of follow-up are considered to 
have completely withdrawn their consent to participate in the trial. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
66 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.8.3.4 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigator or 
subinvestigator will be given instructions to meet and discuss with the subject their 
options of continuing in the trial, preferably on therapy. The investigator or 
subinvestigator should ensure understanding and documentation of the reasons for the 
subject’s desire to withdraw consent. 
3.9 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on treatment, 
whether through randomization or open assignment. 
Subjects who signed the ICF but were not subsequently allocated to a trial treatment are 
eligible for rescreening. In the event that the screening examination is again performed, a 
new written consent must be obtained and a new subject identifier assigned before 
rescreening. 
The following information will be recorded in the CRF of a screen failure subject. 
• Date of informed consent 
• Date of investigation 
• Sex 
• Date of birth 
• Race 
• Ethnicity 
• Nationality 
• Whether the inclusion criteria were satisfied (each criterion number the subject failed 
to meet will be specified) 
• Whether the subject fell under any of the exclusion criteria (together with each 
criterion number the subject fell under) 
• Date screen failure was confirmed 
• Reason for screen failure assessment 
 
3.10 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
received all doses of the IMP. Subjects who complete the end-of-trial examination 
scheduled on the last day of the treatment period will be defined as trial completers. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
67 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
3.11 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before the last scheduled contact, who do not 
have a known reason for discontinuation (eg, withdrew consent or AE), and for whom a 
survival status at the end of the trial cannot be determined will be classified as “lost to 
follow-up” as the reason for discontinuation. 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, records of direct contact with the 
subject, medical records, records of successful telephone contact with the subject, 
statement by a family member or primary care physician, or public records). 
The investigator or subinvestigator, or designee will make 3 documented attempts to 
contact the subject by telephone and in the event the investigator or designee is unable to 
reach the subject by telephone, the investigator or subinvestigator, or designee will 
attempt to contact the subject via certified mail or an alternative similar method, where 
appropriate, before assigning a “lost to follow-up” status. 
The investigator or subinvestigator will document the following information about the 
subject lost to follow-up in source documents and CRF: 
• Last date of contact or contact attempt 
• Investigation method 
• Whether or not the subject is reached 
• Presence/absence of an AE(s), together with each AE term, date of occurrence and 
date of resolution, severity, and relationship to the IMP if present 
• Action taken regarding the IMP administration, action taken for AE(s), outcome of 
AE(s) 
 
3.12 
Subject Compliance 
The subject will remain under the supervision of the investigator or subinvestigator 
during the trial period. The investigator or subinvestigator will instruct the subject to 
comply with the following restrictions: 
• The IMP and coadministered diuretics should be taken according to the instructed 
dose and regimen. 
• The trial schedule should be followed during the trial. 
• Prohibited concomitant drugs (see Section 4.1 Prohibited Medications) must not be 
used. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
68 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
• The dose(s)/regimen(s) of restricted concomitant drugs (see Section 4.2 Restricted 
Concomitant Drugs, etc.) should not be modified. 
• Any information acquired through participation in the trial must not be disclosed to 
any third person. 
 
3.13 
Protocol Deviations 
The investigator or subinvestigator will not deviate from or change the protocol without a 
prior written agreement between the investigator and sponsor and also a prior written IRB 
approval issued after review by the IRB. 
However, when a deviation from or change to the protocol is medically necessary to 
eliminate immediate hazards to the subjects, the investigator or subinvestigator may 
deviate from or change the protocol without a prior written agreement with the sponsor or 
a prior written IRB approval. When the investigator deviates from or changes the 
protocol without a prior written agreement with the sponsor or a prior written IRB 
approval, he/she promptly submits a document describing the deviation or change and the 
reason for the deviation or change to the sponsor and the head of trial site and obtains the 
IRB’s approval. The investigator will also obtain the sponsor’s agreement via the head of 
trial site after obtaining approval from the head of trial site. 
(1) Reporting to the Sponsor 
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 or subinvestigator, or designee will 
contact the sponsor at the earliest possible time by telephone. The investigator or 
subinvestigator and sponsor will come as quickly as possible to a joint decision regarding 
the subject’s continuation in the trial. This decision will be documented by the 
investigator or subinvestigator and the sponsor, and reviewed by the site monitor. 
(2) Documenting Deviations 
The investigator or subinvestigator will document all protocol deviations in source 
documents. 
For the protocol deviations specified in the protocol, all the required information will be 
documented in the CRF according to the sponsor’s procedure for CRF preparation. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
69 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
4 
Restrictions 
4.1 
Prohibited Medications 
Use of the drugs named in Table 4.1-1 will be prohibited from the run-in period to the 
end-of-trial/withdrawal examination. 
Table 4.1-1 
Prohibited Concomitant Drugs 
1 
Vasopressin antagonist 
2 
The following heart failure medications (injections) 
a) Human atrial natriuretic peptide 
b) Phosphodiesterase III inhibitor 
c) Catecholamine 
d) Colforsin 
3 
Diuretic injections 
4 
Drugs and food that may inhibit or induce Cytochrome P450 (CYP)3A4 (see Table 4.1-2) 
5 
Drugs unapproved in Japan, including IMP other than OPC-61815 
 
 
[Rationale for prohibited concomitant drugs] 
1, 2 
Use of these drugs can make efficacy evaluation difficult. 
3 
Patients who are receiving common treatment for cardiac edema (loop diuretics equivalent to 
furosemide at dose of 40 mg/day or higher, a combination of a loop diuretic(s) and thiazide 
diuretic(s), or a combination of a loop diuretic(s) and aldosterone antagonist(s); all of these drugs 
must be orally administered) are the target population of this trial. 
4 
Use of such drugs and food can make pharmacokinetic, safety, and efficacy evaluation difficult. 
5 
The safety of such drugs in the Japanese population has not been established. 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
70 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Table 4.1-2 
Drugs and Food That Induce or Inhibit CYP3A4 
Category 
Drugs/Food 
(1) CYP3A4 inhibitor (excluding 
topical preparation) 
 
Antimicrobial agents 
Clarithromycin, erythromycin, fluconazole, itraconazole, 
miconazole, norfloxacin, chloramphenicol, voriconazole, 
ciprofloxacin 
Anti-HIV drugs 
Atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, lopinavir, 
telaprevir, fosamprenavir, cobicistat, darunavir, elvitegravir 
Drugs for viral liver diseases 
Ombitasvir/paritaprevir/ritonavir 
Calcium antagonists 
Diltiazem, verapamil 
Antidepressants 
Fluvoxamine 
Agents for peptic ulcer 
Cimetidine 
Anticancer drugs 
Imatinib, crizotinib 
Immunosuppressants 
Ciclosporin 
Antiemetics 
Aprepitant 
Others 
Tofisopam, istradefylline, clotrimazole 
Foods 
Grapefruit, star fruit, Seville orange, and their products (eg, juice) 
(2) CYP3A4 inducer (excluding 
topical preparation) 
 
Barbiturates 
Phenobarbital, amobarbital, pentobarbital, barbital, secobarbital, 
primidone 
Adrenocortical hormones 
Cortisone, hydrocortisone, prednisolone, methylprednisolone, 
triamcinolone, dexamethasone, betamethasone, paramethasone, 
fludrocortisone 
Antihypertensive drugs 
Bosentan 
Anti-HIV drugs 
Efavirenz, etravirine, nevirapine 
Antiepileptic drugs 
Carbamazepine, phenytoin, oxcarbazepine 
Antitubercular agents 
Rifampicin, rifabutin 
Anticancer drugs 
Enzalutamide, mitotane 
Others 
Modafinil 
Foods 
Foods containing St. John's wort 
 
4.2 
Restricted Concomitant Drugs, etc. 
Subjects may use drugs (other than OPC-61815 and tolvaptan) and therapies under the 
following conditions from the run-in period to the end-of-trial (or withdrawal) 
examination: 
1) Diuretics other than vasopressin antagonists may be used if the dose and regimen 
are kept unchanged from the start of the run-in period to the end-of-trial (or 
withdrawal) examination. 
2) The drugs that may affect fluid retention or underlying disease (specified in Table 
4.2-1) may be used if the dose and regimen are kept unchanged. 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
71 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Table 4.2-1 
Restricted Concomitant Drugs and Therapies 
1 
Infusion solutions (no restriction applies if used as the solvent of a drug(s)) 
2 
Potassium supplements 
3 
Xanthine 
4 
Nonsteroidal anti-inflammatory drugs (excluding one used as needed or used topically) 
5 
Antihypertensive agents 
6 
Heart failure drugs other than the prohibited concomitant drugs 
 
3) Salt content in meals must not be changed in subjects on diet therapy (salt 
restriction). 
 
[Rationale for Restricted Concomitant Drugs/Therapies] 
1) to 3) These are set to control the diuretic effect and the effects on electrolyte concentration of drugs 
(other than the IMP) and diet therapy (salt restriction). 
 
5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. AEs would not include information recorded as medical 
history at screening for pre planned procedures for which the underlying condition was 
known and no worsening occurred. An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. 
An SAE includes any event that results in any of the following outcomes: 
• Death 
• Life-threatening; ie, the subject was, in the opinion of the investigator or 
subinvestigator, at immediate risk of death from the event as it occurred. It does not 
include an event that, had it occurred in a more severe form, might have caused death. 
• Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions. 
• Requires in-patient hospitalization or prolongs hospitalization. 
− Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
72 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
− Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs. 
• Congenital anomaly/birth defect. 
• Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse. 
 
Nonserious adverse events are all AEs that do not meet the criteria for a "serious" AE. 
Immediately Reportable Event (IRE):  
• Any SAE. 
• Any AE related to occupational exposure. 
• Potential Drug Induced Liver Injury (DILI) case (see Section 5.4).  
• Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be documented on the AE CRF if 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 all laboratory tests as they become available. This 
review will be documented by the investigator’s or subinvestigator’s dated signature on 
the laboratory report. For each abnormal laboratory test result, the investigator or 
subinvestigator needs to ascertain if this is an abnormal (ie, clinically significant) change 
from baseline for that individual subject. This determination, however, does not 
necessarily need to be made the first time an abnormal value is observed. The 
investigator or subinvestigator may repeat the laboratory test or request additional tests to 
verify the results of the original laboratory tests. If this laboratory value is considered 
medically relevant by the investigator or subinvestigator (subject is symptomatic, 
requiring corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the CRF. The intensity of an adverse experience is defined as follows: 
1 = Mild:  
Discomfort noticed, but no disruption to daily activity. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
73 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
2 = Moderate: 
Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: 
Inability to work or perform normal daily activity. 
 
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE. 
Not Related:  
There is no temporal or causal relationship between the IMP and 
the AE. 
5.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will periodically assess subjects for the occurrence of 
AEs. To avoid bias in eliciting AEs, subjects should be asked the non-leading question: 
“How have you felt since your last visit?” All AEs (serious and nonserious) reported by 
the subject must be recorded on the source documents and CRFs provided by the sponsor. 
AE and serious AE collection is to begin after a subject has signed the ICF. 
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition. 
In addition, the sponsor must be notified immediately by e-mail of any IREs according to 
the procedure outlined below, in Section 5.3. Special attention should be paid to 
recording hospitalization and concomitant medications. 
The following information will be documented in the CRF according to the sponsor’s 
procedure for CRF preparation. 
• Event term 
• Date (and time, if known, during hospitalization) of occurrence and date of resolution 
• Severity 
• Seriousness (together with detailed description of the event if serious) 
• Causal relationship to the IMP 
• Action taken regarding IMP administration 
• Outcome 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
74 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
5.3 
Immediately Reportable Events  
The investigator or subinvestigator must immediately report after either the investigator 
or subinvestigator or site personnel become aware of any SAE, DILI, or confirmed 
pregnancy, by e-mail to the sponsor using the contact information on the cover page of 
this protocol. An IRE form must be completed and sent by e-mail to the sponsor. 
Subjects experiencing SAEs should be followed clinically until the events are resolved, 
the condition is considered clinically stable, or the subject is lost to follow-up. Resolution 
means that the subject has returned to the baseline state of health and stabilized means 
that the investigator or subinvestigator does not expect any further improvement or 
worsening of the subject’s condition. It is expected that the investigator or 
subinvestigator will provide or arrange appropriate supportive care for the subject and 
will provide prompt updates on the subject’s status to the sponsor. 
5.4 
Potential Drug-Induced Liver Injury 
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is ≥3 times the upper limit of normal (ULN), a total 
bilirubin level should also be evaluated. If the total bilirubin is ≥2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the CRF. 
5.5 
Pregnancy 
Women of child-bearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 
12 months). 
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures to prevent 
pregnancy during the course of the trial and for 30 days after the last administration of 
IMP. Unless the subject is sterile (ie, women who have had a bilateral oophorectomy 
and/or hysterectomy or who have been postmenopausal for at least 12 consecutive 
months; or men who have had a bilateral orchidectomy) or remains abstinent, either of 
the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, 
intrauterine device, birth control pills, or condom with spermicide. 
Before enrolling WOCBP in this clinical trial, the investigator or subinvestigator must 
review the below guidelines about trial participation with all WOCBP. The topics should 
generally include: 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
75 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
• General information 
• Informed consent form 
• Pregnancy prevention information 
• Drug interactions with hormonal contraceptives 
• Contraceptives in current use 
• Guidelines for the follow-up of a reported pregnancy 
 
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form stating that the above-
mentioned risk factors and the consequences were discussed with her. 
A urine pregnancy test for hCG will be performed at screening on all WOCBP. If a urine 
test is performed and is positive, the investigator or subinvestigator will follow up with a 
confirmatory serum test. 
During the trial, all WOCBP should be instructed to contact the investigator or 
subinvestigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual cycle). 
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. 
The investigator or subinvestigator must immediately notify the sponsor of any 
pregnancy associated with IMP exposure during the trial and for 30 days after the last 
administration of IMP, and record the event on the IRE form and forward it to the 
sponsor. The sponsor will forward Pregnancy Surveillance Form(s) for monitoring the 
outcome of the pregnancy. 
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered, if indicated. In addition, the 
investigator or subinvestigator must report to the sponsor, on appropriate Pregnancy 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
76 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Surveillance Form(s), follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome. Infants will be followed for a minimum of 6 
months from the date of birth. 
5.6 
Procedure for Breaking the Blind 
The investigator or subinvestigator is encouraged to contact the sponsor to discuss their 
rationale for unblinding. However, to prevent delays to the investigator or 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 (ie, the investigator or subinvestigator will be able to obtain the code break 
information independent of the sponsor). The investigator or subinvestigator may access 
the code breaking information via the IWRS. Documentation of breaking the blind should 
be recorded in the subject’s medical record with the date and time the blind was broken 
and the names of the personnel involved. Once the blind is broken for a subject, that 
subject may not reinitiate treatment with the IMP. 
5.7 
Follow-up of Adverse Events After Treatment Period 
In this trial, collection of AEs will continue until the post-treatment follow-up scheduled 
to occur between 7 and 10 days after the final IMP administration (Day 12 to 15). After 
the trial completion, AEs that meet any of the cases described in Section 5.7.1 Follow-up 
of Nonserious Adverse Events, Section 5.7.2 Follow-up of Serious Adverse Events, 
and Section 5.7.3 Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact will also be followed up as specified in the relevant section. 
5.7.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE CRF with the current status noted. If a subject has an AE or has not recovered from 
an AE at the last scheduled contact, follow-up contacts will be scheduled at least every 
4 weeks until resolution of the AE is confirmed, the condition is considered clinically 
stable, or the subject is lost to follow-up. All nonserious events that are ongoing at the 
last scheduled contact will be recorded as ongoing on the CRF. For any AE having been 
identified throughout the trial, during analysis, additional relevant medical history 
information may be requested to further ascertain causality (including, but not limited to, 
information such as risk-related behavior, family history and occupation). The follow-up 
information after the last scheduled contact will be recorded in the subject’s medical 
record. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
77 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
5.7.2 
Follow-up of Serious Adverse Events 
This trial requires that subjects be actively monitored for SAEs up to the last scheduled 
contact. 
Serious AEs that are identified or ongoing at the last scheduled contact must be 
recorded on the AE CRF page and reported to the sponsor according to the reporting 
procedures outlined in Section 5.3. This may include unresolved previously reported 
SAEs, or new SAEs. All serious adverse events that are ongoing at the last scheduled 
contact will be recorded as ongoing on the CRF. The investigator or subinvestigator will 
follow SAEs until the events are resolved, the condition is considered clinically stable, or 
the subject is lost to follow-up. The investigator or subinvestigator will continue to report 
any significant follow-up information to the sponsor using the IRE form up to the point 
the event has been resolved, the condition is considered clinically stable, or the subject is 
lost to follow-up. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring 
after Last Scheduled Contact 
Any new SAEs reported by the subject to the investigator or subinvestigator that occur 
after the last scheduled contact, and are determined by the investigator or 
subinvestigator to be reasonably associated with the use of the IMP, should be reported to 
the sponsor. This may include SAEs that are captured on follow-up telephone contact or 
at any other time point after the defined trial period (ie, up to last scheduled contact). The 
investigator or subinvestigator should follow SAEs identified after the last scheduled 
contact until the events are resolved, stabilized, or the subject is lost to follow-up. The 
investigator or subinvestigator should continue to report any significant follow-up 
information to the sponsor until the event is resolved, the condition is considered 
clinically stable, or the subject is lost to follow-up with the IRE form. 
6 
Pharmacokinetic/pharmacodynamic/pharmacogenomic 
Analysis 
6.1 
Pharmacokinetics 
This section only describes the primary and secondary pharmacokinetic endpoints. 
6.1.1 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set will include all subjects treated with the IMP at least 
once and have at least one evaluable plasma drug concentration measurement after IMP 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
78 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
administration. However, subjects whose data are rejected entirely after assessment 
according to the step in Section 6.1.2(3)1) will be excluded from the analysis set. 
6.1.2 
Pharmacokinetic Analysis 
(1) Endpoints 
(a) Primary Endpoint: 
1) Cmax and AUC24h of plasma tolvaptan on Day 1 of treatment period 
(b) Secondary Endpoints 
1) Plasma concentrations of OPC-61815, tolvaptan, DM-4103, and DM-4107 
2) Plasma pharmacokinetic parameters of OPC-61815, tolvaptan, DM-4103, and 
DM-4107 
• Day 1 of treatment period: Cmax,#1 AUC24h,#1 AUCt, AUC∞, tmax, λz, 
AUC_%Extrap, tlast, t1/2,z, CL,#2 CL/BW,#2 V,#2 CL/F,#3 CL/F/BW#3 
• Day 1, Day 2, Day 3, Day 4, and Day 5 of treatment period: C24h 
• Day 5 of treatment period: R5,ac (C24h) 
#1: Excluding tolvaptan 
#2: Calculated only for OPC-61815 after administration of OPC-61815 injection 
#3: Calculated only for tolvaptan after administration of tolvaptan 15-mg tablet 
3) Ratio of the AUC of metabolite to that of OPC-61815#4 
Day 1 of treatment period: AUC∞, AUC24h, and AUCt 
#4: Calculated only for the OPC-61815 injection groups 
(2) Dataset for Analysis 
Pharmacokinetic analysis set 
(3) Analysis Method 
1) Acceptance or nonacceptance of data will be determined in accordance 
with Section 3.4 Exclusion From Pharmacokinetic Analysis of the Manual 
Standard Practice for Noncompartmental Pharmacokinetic Analysis (Version 
1.0).11 
2) For each parameter specified under Section 6.1.2(1)(a) “Primary endpoints 1),” 
descriptive statistics will be calculated for each group. For Section 6.1.2(1)(b) 
“Secondary endpoints 1),” descriptive statistics will be calculated by date of 
administration, compound, and group at each blood sampling time point. For each 
parameter of Section 6.1.2(1)(b) “Secondary endpoints 2),” descriptive statistics 
will also be calculated by date of administration, compound, and group. 
Descriptive statistics calculated will include number of subjects, arithmetic mean, 
standard deviation, coefficient of variation, minimum, median, and maximum for 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
79 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
plasma drug concentration and number of subjects, arithmetic mean, standard 
deviation, coefficient of variation, geometric mean, minimum, median, and 
maximum for other than plasma drug concentration. Descriptive statistics will be 
calculated only for the groups in which over 50% of subjects have the data. 
3) For each parameter of Section 6.1.2(1)(a) “Primary endpoint 1),” the difference 
(each OPC-61815 injection group − tolvaptan 15-mg group) in mean value and its 
95% confidence interval will be calculated using logarithmic transformation 
(natural logs). 
 
6.2 
Pharmacodynamics 
Analyses will be performed in the pharmacodynamic analysis set (see Section 7.2 
Datasets for Analysis). 
For each of the endpoints listed below, descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median, and maximum) of the measurement and the 
change from baseline will be calculated for each group at each time point after the start of 
IMP administration. For daily urine volume, daily fluid intake, and daily fluid balance 
after IMP administration on Day 1 and after final IMP administration, the difference 
(each OPC-61815 injection group − tolvaptan 15-mg tablet) in mean change from 
baseline and its 95% confidence interval will be calculated. 
• Serum sodium concentration, serum potassium concentration 
• Serum osmolality 
• Biomarkers (plasma BNP concentration, serum NT-proBNP concentration, serum 
troponin concentration, plasma AVP concentration, plasma renin activity) 
• Daily urine volume 
• Daily fluid intake 
• Daily fluid balance 
• Daily urine sodium excretion 
• Daily urine potassium excretion 
• Urine osmolality 
 
6.3 
Pharmacokinetics/Pharmacodynamics 
No pharmacokinetic/pharmacodynamic analyses are planned. 
6.4 
Pharmacogenomics 
See Section 3.7.5.3.1(4) for analyses related to pharmacogenomic. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
80 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
7 
Statistical Analysis 
7.1 
Sample Size 
The primary objective of this clinical trial is to compare tolvaptan exposure in order to 
investigate the dose of OPC-61815 injection required to achieve exposure equivalent to 
tolvaptan 15-mg tablet for use in conducting phase 3 confirmatory clinical trials of OPC-
61815. The number of subjects required for this purpose was determined to be at least 10 
subjects per group (50 subjects in total) who complete blood sampling for measurement 
of plasma drug concentrations up until 24 hours postdose on Day 1. In consideration of 
the possibility of some subjects withdrawing from the trial prior to 24 hours postdose on 
Day 1, the approximate target number of subjects for the start of IMP administration is 
set at 11 subjects per group (55 subjects in total). 
7.2 
Datasets for Analysis 
The safety analysis set will include all subjects treated with the IMP at least once. 
The efficacy analysis set will include all subjects treated with the IMP at least once and 
have body weight data after IMP administration. 
The pharmacodynamic analysis set will include all subjects treated with the IMP at least 
once and have pharmacodynamic data after IMP administration. 
7.3 
Handling of Missing Data 
The last observation before the day after final IMP administration will be carried forward 
if the measurement of the day after final IMP administration is missing. 
7.4 
Analysis of Efficacy Endpoints 
The following analyses will be performed in the efficacy analysis set. 
7.4.1 
Body Weight 
Analysis of covariance using baseline weight (before IMP administration on Day 1) as 
covariate will be performed on the change (absolute change and percent change) from 
baseline in body weight after final administration (the day after final IMP administration) 
to calculate the least-square mean of the difference between each OPC-61815 injection 
group and tolvaptan 15-mg tablet group and its 95% confidence interval. At each time 
point, descriptive statistics of measurement and change (absolute change and percent 
change) from baseline will be calculated for each group. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
81 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
7.4.2 
Congestive Symptoms 
7.4.2.1 
Lower Limb Edema, Other Edema, and Pulmonary Congestion 
(Chest X-ray Finding) 
The proportion of responders (subjects with a “markedly improved” or “improved” 
response is evaluated with reference to Table 7.4.2.1-1) and the proportion of subjects 
who achieve resolution [subjects who have congestive symptoms at baseline 
(immediately before first IMP administration) and in whom the symptoms resolve after 
IMP administration] of lower limb edema, other edema, and pulmonary congestion after 
final administration are calculated for each OPC-61815 injection group, together with the 
difference in the proportions between each OPC-61815 injection group and tolvaptan 15-
mg group with the 95% confidence interval of each difference. 
Changes in the severity of each congestive symptom at each time point (from baseline to 
after each administration and to after final administration) will be summarized for each 
group in a shift table. 
Table 7.4.2.1-1 
Response of Lower Limb Edema, Other Edema, and 
Pulmonary Congestion 
 
Response 
Description 
1 
Markedly improved 
Resolution of symptom or improvement by 2 grades or more 
2 
Improved 
Improvement by 1 grade (if the symptom has resolved, an 
assessment of “markedly improved” is given instead) 
3 
No change 
No change in symptom, or absence of symptom throughout the trial 
4 
Worsened 
Worsening by 1 grade or more 
 
7.4.2.2 
Jugular Venous Distension, Hepatomegaly, and Cardiothoracic 
Ratio 
Change from baseline (immediately before first IMP administration) in jugular venous 
distension, hepatomegaly, and cardiothoracic ratio after final administration will be 
analyzed using analysis of covariance with baseline value as covariate to calculate the 
least square mean of the difference between each OPC-61815 injection group and 
tolvaptan 15-mg tablet group and its 95% confidence interval. Descriptive statistics of the 
measurements and their changes from baseline at each time point will be calculated for 
each group. 
7.4.2.3 
Pulmonary Rales and Third Cardiac Sound 
The proportion of subjects who achieve resolution of pulmonary rales and third cardiac 
sound [subjects who have the sign at baseline (immediately before first IMP 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
82 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
administration) and who do not have the sign after IMP administration] will be calculated 
in each OPC-61815 injection group together with the difference in the proportion 
between each OPC-61815 injection group and tolvaptan 15-mg group and its 95% 
confidence interval. 
Changes in the severity of pulmonary rales and third cardiac sign at each time point (from 
baseline to after each IMP administration and to after final administration) will be 
summarized for each group in a shift table. 
7.4.3 
NYHA Classification 
Changes in NYHA classification at each time point (from baseline [immediately before 
first IMP administration] to after each administration and to after final administration) 
will be summarized for each group in a shift table. 
7.5 
Analysis of Demographic and Baseline Characteristics 
A frequency distribution table will be created by group for subject demographic and other 
baseline characteristics for the pharmacokinetic and safety analysis sets. Descriptive 
statistics of demographic and other baseline characteristics will also be calculated for 
each group in the pharmacokinetic and safety analysis sets. 
7.6 
Safety Analysis 
The following analyses will be performed for each group and IMP in the safety analysis 
set. 
7.6.1 
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  
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
83 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
7.6.2 
Clinical Laboratory Data 
Descriptive statistics of clinical laboratory values (excluding qualitative urinalysis) as 
well as of the changes from baseline (before IMP administration on Day 1) in values at 
each time point and after final administration will be calculated. The results of qualitative 
urinalysis at each postdose time point and after final administration compared with 
baseline results will be summarized in a shift table. Each clinical laboratory value 
excluding qualitative urinalysis will be categorized into “within reference range,” “below 
the lower limit of reference range,” or “above the upper limit of reference range” using 
standard values to generate a shift table summarizing laboratory data at each postdose 
time point and after final administration compared with baseline. 
7.6.3 
Vital Signs Data 
Descriptive statistics will be calculated for vital signs together with the changes from 
baseline (immediately before first IMP administration) at each time point and after final 
administration. 
7.6.4 
Electrocardiogram Data 
Descriptive statistics of each 12-lead ECG parameter and the changes from baseline (run-
in period) in each parameter at each time point and after final administration will be 
calculated. 
The number and percentage of subjects who have a QTc interval (QTcB, QTcF) of 
“> 450,” “> 480,” and “> 500” between baseline and after final administration will be 
calculated. In addition, the number and percentage of subjects who show a change of 
“> 30” and “> 60” in QTc interval from baseline at each postdose time point or after final 
administration are calculated. "Normal” and “abnormal” assessments at each postdose 
time point and after final administration compared with baseline will be summarized in a 
shift table. 
8 
Management of Investigational Medicinal Product 
For full details on IMP management, please refer to the OPC-61815 IB and the Clinical 
Operation Manual. 
8.1 
Packaging and Labeling 
Trial medication will be provided to the IMP manager by the sponsor or designated agent. 
IMPs will be provided as subject kits. Each kit consists of 8 vials of OPC-61815 injection 
(2 mg, 4 mg, 8 mg, 16 mg, or placebo) and a small box containing a blister sheet of 10 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
84 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
tolvaptan tablets (15-mg tablet or placebo). A label stating that the content is for clinical 
trial use, protocol number, IMP names, quantity, lot number, expiration date, storage 
conditions, and sponsor’s name and address will be affixed to each vial and small box. 
Each subject kit also displays the statement that the content is for clinical trial use, 
protocol number, drug number, IMP names, quantity, lot number, expiration date, storage 
conditions, subject identifier, and sponsor’s name and address. 
8.2 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to IMP manager, the person responsible for IMP preparation at the trial site (non-blinded 
staff), to prevent any other person from preparing the drugs. The IMP manager must not 
provide IMP to any subject not participating in this protocol. 
The IMP will be stored at room temperature. The clinical site staff will maintain a 
temperature log in the IMP storage area recording the temperature at least once each 
working day. 
8.3 
Accountability 
The IMP manager must maintain an inventory record of IMP received, dispensed, 
administered, and returned. 
8.4 
Returns and Destruction 
Upon completion or termination of the trial, all unused and/or partially used IMP must be 
returned to the sponsor or a designated agent. 
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be identified by protocol number with trial site number on the outermost shipping 
container. Returned supplies should be in the original packages. The assigned trial 
monitor will facilitate the return of unused and/or partially used IMP. 
8.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving: 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
85 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
• Failure/malfunction of a product to meet any of its specifications 
• Incorrect or missing labeling 
• Packaging issues (eg, damaged, dirty, crushed, missing product) 
• Blister defects (eg, missing, empty blisters) 
• Bottle defects (eg, under/over-fill, no safety seal) 
• Vial defects 
• Product defect (eg, odor, chipped, broken, embossing illegible) 
• Loss or theft of product 
 
8.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator or subinvestigator, or designee must record all PQCs identified through 
any means from the receipt of the IMP from the sponsor, or sponsor’s designee, through 
and including reconciliation and up to destruction, including subject dosing. The 
investigator or subinvestigator, or designee must notify the sponsor (or sponsor’s 
designee) by e-mail (PQC_263-102-00001@otsuka.jp) immediately after becoming 
aware of the PQC according to the procedure outlined in Section 8.5.2 (Information 
Required for Reporting Product Quality Complaints). 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow the reporting mechanisms listed above. 
Precautions should be taken to maintain blinding at the trial site when reporting PQC. 
8.5.2 
Information Required for Reporting Product Quality Complaints 
• Description of compliant 
• Reporter identification (eg, subject, investigator or subinvestigator, trial site, whether 
blinded [IMP preparer] or not) 
• Reporter contact information (eg, address, phone number, e-mail address) 
• ID of material (product/compound name, drug number) 
• Clinical protocol reference (number and/or trial name) 
• Dosage form/strength (if known) 
• Pictures (if available) 
• Complaint sample availability for return 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
86 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
8.5.3 
Return Process for Product Quality Complaints 
Indicate during the report of the PQC if the complaint sample is available for return. If 
complaint sample is available for return, sponsor will provide instructions for sample 
return, when applicable. 
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
8.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
9 
Records Management 
9.1 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to progress notes, 
electronic data, screening logs, and recorded data from automated instruments. Source 
plasma concentration data will be retained by the bioanalytical laboratory. The sponsor 
will keep the electronic file submitted by the bioanalytical laboratory as a copy. 
All source documents pertaining to this trial other than the above (drug concentration 
data) 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, and regulatory inspection(s) by providing direct access to source data/documents 
by authorized persons as defined in the ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements. 
9.2 
Data Collection 
During each subject’s visit to the clinic, investigator or subinvestigator will record 
progress notes to document all significant observations. At a minimum, these notes will 
contain: 
• Documentation of the informed consent process, including any revised consents; 
• Documentation of the investigator’s or subinvestigator’s decision to enroll the subject 
into the trial, the review of all inclusion/exclusion criteria prior to IMP administration, 
and confirmation of the subject’s actual participation in the trial; 
• The date of the visit and the corresponding Visit or Day in the trial schedule; 
• General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
87 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
investigator’s or 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;  
• The signature (or initials) and date of each investigator or subinvestigator (or 
designee) who made an entry in the progress notes. 
 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by a site staff 
member authorized to make the change. Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data  right data). If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
investigator or subinvestigator. If electronic data systems are being utilized, a full audit 
trail of changes must be maintained. 
Information from the trial progress notes and other source documents will be entered by 
investigative site personnel directly onto electronic CRFs in the sponsor’s electronic data 
capture (EDC) system. Changes to the data will be captured by an automatic audit trail. 
9.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with Section 8 of the ICH GCP Guideline E6 and as required by applicable local 
regulations. The trial site will take measures to prevent accidental or premature 
destruction of these documents. 
9.4 
Records Retention at the Trial Site 
The trial site will retain all trial-related documents and records for the period of time 
indicated below or until the decision to discontinue DNA storage is made, whichever is 
the longest. However, if the sponsor requires a longer period of archiving, the head of the 
trial site will consult with the sponsor on the period and procedures of record retention. 
• The date 2 years after manufacturing and marketing approval date. However, if the 
head of the trial site receives notification from the sponsor that development has been 
terminated or that results of the trial will not be submitted with the approval 
application, the date 3 years after receipt of such notification. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
88 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
• The date 3 years after termination or completion of the trial. 
 
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 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 
Quality Control and Quality Assurance 
10.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators or 
subinvestigators and clinical site personnel will undergo initial and ongoing training for 
this particular trial, and this training will be clearly documented. 
10.2 
Auditing 
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of CRFs with source documents. The 
investigator agrees to 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. 
11 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science (CIOMS) guidelines, and applicable local 
laws and regulations. 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
89 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Each trial site will seek approval/favorable opinion by an IRB according to regional 
requirements, and the trial site will provide that documentation to the sponsor. The IRB 
will evaluate the ethical, scientific and medical appropriateness of the trial. Further, in 
preparing and handling CRFs, the investigator, subinvestigator and their staff will take 
measures to ensure adequate care in protecting subject privacy. To this end, a subject 
number and subject identification code will be used to identify each subject. 
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the trial site. 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 
Subjects will be identified only by unique subject identifier in CRFs. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations. 
13 
Amendment Policy 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “non-substantial” amendments, the investigator or 
subinvestigator will wait for IRB approval/favorable opinion of the amended protocol 
before implementing the change(s). Administrative amendments are defined as having no 
effect on the safety of subjects, conduct or management of the trial, trial design, or the 
quality or safety of IMP(s) used in the trial. A protocol change intended to eliminate an 
apparent immediate hazard to subjects should be implemented immediately, followed by 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
90 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
IRB notification within local applicable timelines. The sponsor will submit protocol 
amendments to the applicable regulatory agencies within local applicable timelines. 
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IRB, repeat written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented. 
14 
Publication Authorship Requirements 
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
91 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
15 
References 
1 
McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of 
congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441-6. 
2 
The Japanese Circulation Society, et al. Guidelines for Treatment of Chronic Heart 
Failure (JCS 2010). 2013. 
3 
The Japanese Circulation Society, et al. Guidelines for Treatment of Acute Heart 
Failure (JCS 2011). 2013. 
4 
Hasunuma T. A placebo-controlled, double-blind, single intravenous dose trial of 
OPC-61815 in healthy adult males (phase 1). Clinical study report. Protocol No. 263-
08-001, issued 30 Aug 2010. 
5 
A study to investigate the safety, tolerance and pharmacokinetics of single rising 
doses of OPC-41061 in healthy male Caucasian subjects (phase 1). Clinical study 
report. Protocol No. 156-95-302, issued 23 Apr 1996. 
6 
Hasunuma T. A single-blind, single oral dose trial of OPC-41061 at 15 to 120 mg in 
healthy adult males to investigate pharmacokinetics, pharmacological action, safety, 
and tolerability (phase 1). Clinical study report. Protocol No. 156-00-001, issued 10 
May 2007. 
7 
Hasunuma T. A single-center, placebo-controlled, double-blind trial of OPC-61815 to 
investigate the safety, pharmacokinetics, and pharmacological action of different 
regimens (phase 1). Clinical study report. Protocol No. 263-10-005, issued 29 Feb 
2012. 
8 
International Conference on Harmonization (ICH) [Internet]. E6:Good Clinical 
Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 Jun; cited 2014 
Dec 5]. Available 
from:http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Effic
acy/E6/E6_R1_Guideline.pdf. 
9 
Forrester JS, Diamond G, Chatterjee K, Swan HJ. Medical therapy of acute 
myocardial infarction by application of hemodynamic subsets (First of two parts). N 
Engl J Med. 1976;295(24):1356-62. 
10 The Criteria Committee of the New York Heart Association, Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Editioned, 1994. 
11 Otsuka Pharmaceutical Co., Ltd. Manual standard practice for noncompartmental 
pharmacokinetic analysis. Version 1.0, issued 24 Dec 2015. 
 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
92 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Appendix 1 
Handling and Shipment of Bioanalytical Samples 
(1) Handling 
Each sample tube for storage is labeled properly. The label should display the protocol 
number, subject number, test parameter(s), sampling time, etc. Each tube should be 
labeled to check the protocol number, subject identifier, test parameter(s), sampling time, 
etc. The actual sampling time should be accurately recorded in the CRF rather than the 
scheduled time of sampling. 
(2) Blood Samples for Pharmacokinetics 
About 2 mL of blood should be collected in an EDTA-coated tube. Normally, venous 
blood should be collected by venous puncture or via an indwelling catheter. Arterial 
blood collected via an indwelling catheter is acceptable if this is judged desirable by the 
investigator or subinvestigator. The tube is gently inverted a few times to mix the content 
and placed in an ice water bath. The tube is immediately (within 45 minutes after 
sampling) centrifuged at about 4°C and approximately 1500 × G for about 10 minutes to 
obtain plasma. Plasma is divided evenly into 2 labeled sample stock tubes (primary 
sample and backup sample) and frozen at −15°C or below. Plasma samples will be 
collected from the trial site by the contract laboratory. The contract laboratory will ship 
plasma samples to the bioanalytical laboratory according to the schedule agreed to with 
the sponsor. Samples are packed in a polystyrene foam box with sufficient dry ice for 
shipment. 
(3) Clinical Laboratory Samples for Pharmacodynamic Evaluation 
The trial site will collect, treat, and store samples according to the sponsor’s procedure. 
• Serum sodium concentration, serum potassium concentration, and serum 
osmolality 
Blood should be collected in a tube for serum separation, and the tube is inverted 
a few times to mix the content. After being left to stand at room temperature for at 
least 30 minutes, the tube is centrifuged to collect serum. The serum is transferred 
to a sample stock tube and refrigerated. 
• Plasma AVP concentration 
Blood should be collected in an EDTA-coated tube, and the tube is inverted a few 
times to mix the content. The tube is centrifuged under cooling, and plasma is 
transferred into a sample stock tube and frozen. 
• Plasma BNP concentration and plasma renin activity 
Blood should be collected in an EDTA-coated tube after the subject has rested in 
the supine position. The tube is then inverted a few times to mix the content. The 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
93 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
tube is centrifuged under cooling, and plasma is transferred into a sample stock 
tube and frozen. 
• Serum NT-proBNP concentration 
Blood should be collected in a tube for serum separation. The tube is inverted a 
few times to mix the content. After being left to stand at room temperature for at 
least 30 minutes, the tube is centrifuged to collect serum. The serum is transferred 
into a sample stock tube and frozen. 
• Serum troponin-I concentration 
Blood should be collected in a tube for serum separation. The tube is inverted a 
few times to mix the content. After being left to stand at room temperature for at 
least 30 minutes, the tube is centrifuged to collect serum. The serum is transferred 
into a sample stock tube and frozen. 
• Urine sodium concentration, urine potassium concentration, and urine osmolality 
An adequate volume of urine is collected from pooled urine in a sample stock 
tube and refrigerated. Urine volume should be measured before sample collection. 
 
(4) Blood Sample for DNA Storage 
Blood collection kit (eg, EDTA-coated tube), instruction for blood treatment and storage, 
and materials for transportation of blood sample are prepared per subject. Two milliliters 
of blood should be collected in an EDTA-coated tube for DNA storage. The tube is 
inverted a few times to mix the content before frozen (at −15°C or below). Trial site will 
follow the instructions specified for the sampling kit for blood collection, treatment, 
storage, and transportation. The contract laboratory will collect blood samples from each 
trial site and ship them to the DNA storage facility. Samples are packed in a polystyrene 
foam box with sufficient dry ice for shipment. 
 
 
 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
94 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Appendix 2 
Protocol Amendment(s)/Administrative Change(s) 
Amendment Number: 
1 
 
Issue Date: 
19 Jun 2017 
 
PURPOSE: Addition of exclusion criteria, correction of trial procedure, and correction 
of errata and omission 
 
BACKGROUND: The protocol is amended based on the PMDA’s inquiries regarding 
the exclusion criteria. Trial procedure (timing of randomization, type of blood sampling) 
is also modified for feasibility reasons. Errata are also corrected. 
 
MODIFICATIONS TO PROTOCOL: 
• Main criteria for exclusion in Synopsis and Table 3.4.4-1 Exclusion Criteria 
“Subjects with a history of hypersensitivity to any of ingredients of OPC-61815 or 
tolvaptan” was added (as a safety precaution). 
• Footnote “a” under Table 3.7-1 Schedule of Observations/Tests and Assessments 
“Randomization normally takes place on Day 1 (or Day -1 if justified. Each subject’s 
fulfillment of the inclusion criterion 8 will be verified on Day 1)” was added (for 
feasibility reasons). 
• 3.7.5.1.1 Pharmacokinetic Blood Samples (2) Blood Sampling and Test Method 
“type of blood collected (venous or arterial)” was added to the information required 
to be recorded in the CRF (for feasibility reasons). 
• 3.7.4.3 Physical Examination and Vital Signs: “Sitting position” (during blood 
pressure measurement) was replaced with “supine position” (erratum). 
• 3.7.4.4 12-lead Electrocardiogram: “He/she then will document ... date and time of 
ECG” was replaced with “He/she then will record ... date of ECG” (erratum). 
• 3.7.5.2.1 Clinical Laboratory Tests for Pharmacodynamic Analysis: A new 
requirement that only venous blood is acceptable was added (for clarification). 
• 3.7.5.3.1 (3) Procedure for Storage: “Venous puncture” was replaced with “venous 
puncture or via indwelling catheter” and “venous blood” with “blood (venous or 
arterial, either is acceptable)” (for feasibility reasons). 
• 3.9 Screen Failures: “Sex” was added to the information required to be recorded in 
the CRF (omission). 
• Appendix 1 (2) Blood Samples for Pharmacokinetics: Text was added to clarify that 
venous blood should normally be collected and that arterial blood is acceptable only 
if it is judged desirable by the investigator or subinvestigator (for feasibility reasons). 
• Appendix 1 (4) Blood sample for DNA storage: “without further treatment” was 
deleted. (erratum) 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
95 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
• Correction of email address (erratum) 
Immediately Reportable Event: IRE_263-102-00001@otsuka.jp 
Email address for reporting PQC: PQC_263-102-00001@otsuka.jp 


 
 
Protocol 263-102-00001 
 
Confidential - Proprietary Information 
 
 
96 
Version 1.0, 08 May 2017 
Amdt. 1: 19 Jun 2017 
Agreement 
I, the undersigned 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-61815, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) responsible for 
such matters in the clinical trial facility where OPC-61815 will be tested prior to commencement of 
this trial. I agree to adhere strictly to the attached protocol (unless amended in the manner set 
forth in the sponsor's Clinical Trial Agreement, at which time I agree to adhere strictly to the 
protocol as amended). 
 
I understand that this IRB-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on case report forms by me and my 
staff will be utilized by the sponsor in various ways, such as for submission to governmental 
regulatory authorities and/or in combination with clinical data gathered from other research sites, 
whenever applicable. I agree to allow sponsor and designee monitors and auditors full access to 
all medical records at the research facility for subjects screened or enrolled in the trial. 
 
I agree to await IRB approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB within the required local applicable timelines. 
Administrative changes to the protocol will be transmitted to the IRB for informational purposes 
only, if required by local regulations. 
 
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and subinvestigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result. 
 
____________________________ 
_____________________________ 
Investigator Print Name  
 
Trial Site Name 
 
_____________________________ 
DD Mon YYYY 
Signature 
 
 
 
Date 
 
This agreement has been signed electronically. The electronic signature page is attached to this 
agreement. 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group Comparison 
Clinical Pharmacology Trial to Investigate the Dose of OPC-61815 Injection Equivalent  
to Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure] 
 
 
 
 
 
NCT Number: NCT03254108 
PRT NO.: 263-102-00001 
Version Date: 21 June 2018 (Version 1.0) 


 
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational Medicinal Product  
OPC-61815 
 
 
 
Protocol No. 263-102-00001 
 
 
A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group Comparison 
Clinical Pharmacology Trial to Investigate the Dose of OPC-61815 Injection Equivalent 
to Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure 
 
Statistical Analysis Plan 
 
Version: Final 1.0 
Date: June 21, 2018 
Protocol Version 2 Date: June 19, 2017  
 
 
 
 
 
 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd.  
 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
2 of 43 
Version 1.0 Date: 06/21/2018 
Table of Contents 
Table of Contents ........................................................................................... 2 
List of Appendices.......................................................................................... 4 
List of Abbreviations and Definition of Terms ........................................... 5 
1 
Introduction .......................................................................................... 7 
2 
Trial Objectives ..................................................................................... 7 
3 
Trial Design ........................................................................................... 7 
3.1 
Type/Design of Trial ...........................................................................................7 
3.2 
Trial Treatments ..................................................................................................8 
3.3 
Trial Population ...................................................................................................8 
3.4 
Handling of Time Points .....................................................................................8 
4 
Sample Size ............................................................................................ 9 
5 
Statistical Analysis Sets ........................................................................ 9 
5.1 
Pharmacokinetic Analysis Set .............................................................................9 
5.2 
Efficacy Analysis Set ........................................................................................10 
5.3 
Safety Analysis Set ............................................................................................10 
5.4 
Pharmacodynamic Analysis Set ........................................................................10 
5.5 
Handling of Missing Data .................................................................................10 
6 
Primary and Secondary Endpoints: ................................................. 10 
6.1 
Primary Endpoint ..............................................................................................10 
6.2 
Secondary Endpoints .........................................................................................10 
7 
Disposition and Demographic Analysis ............................................ 11 
7.1 
Subject Disposition............................................................................................11 
7.2 
Demographic and Baseline Characteristics .......................................................11 
7.3 
Baseline Disease Evaluation .............................................................................12 
7.4 
Treatment Compliance ......................................................................................13 
7.5 
Prior and Concomitant Medications ..................................................................13 
7.6 
Protocol Deviations ...........................................................................................14 
8 
Efficacy Analysis ................................................................................. 14 
8.1 
Body Weight......................................................................................................14 
8.2 
Congestive symptoms........................................................................................15 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
3 of 43 
Version 1.0 Date: 06/21/2018 
8.2.1 
Lower limb Edema, Other Edema, and Pulmonary Congestion (Chest 
X-ray) ..............................................................................................................15 
8.2.2 
Jugular Venous Distension, Hepatomegaly, and Cardiothoracic Ratio ..........15 
8.2.3 
Pulmonary Rales and Third Cardiac Sound ....................................................16 
8.2.4 
NYHA Classification ......................................................................................16 
8.3 
Subgroup Analyses ............................................................................................16 
9 
Safety Analyses ................................................................................... 16 
9.1 
Extent of Exposure ............................................................................................16 
9.2 
Adverse Events ..................................................................................................16 
9.3 
Clinical Laboratory Data ...................................................................................17 
9.4 
Vital Sign Data ..................................................................................................17 
9.5 
Electrocardiogram Data .....................................................................................18 
10 
Pharmacokinetic Analyses ................................................................. 18 
11 
Pharmacodynamic Analyses .............................................................. 22 
12 
Pharmacogenomic Analyses .............................................................. 23 
13 
Interim Analysis .................................................................................. 23 
14 
Changes in the Planned Analyses ...................................................... 23 
15 
References ............................................................................................ 24 
 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
4 of 43 
Version 1.0 Date: 06/21/2018 
List of Appendices 
Appendix 1 
List of Tables and Figures............................................................. 25 
Appendix 2 
List of Subject Data ...................................................................... 40 
Appendix 3 
Molecular Weight and Quantitation Limit of Plasma Drug 
Concentration ................................................................................ 43 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
5 of 43 
Version 1.0 Date: 06/21/2018 
List of Abbreviations and Definition of Terms 
Abbreviation Definition 
AE 
Adverse event 
AVP 
Arginine vasopressin 
BNP 
Brain natriuretic peptide 
CHF 
Congestive heart failure 
CRF 
Case report form 
IMP 
Investigational medicinal product 
MedDRA 
Medical Dictionary for Regulatory Activities 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
TEAE 
Treatment-emergent adverse event 
 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
6 of 43 
Version 1.0 Date: 06/21/2018 
Pharmacokinetics Parameter Table 
Abbreviation 
and Term 
Unit 
Unabbreviated Expression or Definition 
AUC∞ 
ng·h/mL 
Area under the concentration-time curve from time zero to infinity 
AUC24h 
ng·h/mL 
Area under the concentration-time curve from time zero to 24 hours 
AUCt 
ng·h/mL 
Area under the concentration-time curve calculated to the last 
observable concentration at time t 
AUC_%Extrap 
% 
Percentage of AUC due to extrapolation from tlast to infinity [(AUC∞ 
− AUCt)/AUC∞ × 100] 
C24h 
ng/mL 
Concentration of drug in the plasma at 24 hours 
CL 
L/h 
Total body clearance of drug from the plasma 
CL/BW 
L/h/kg 
CL normalized in body weight 
CL/F 
L/h 
Apparent clearance of drug from plasma after extravascular 
administration   
CL/F/BW 
L/h/kg 
CL/F normalized in body weight 
Cmax 
ng/mL 
Maximum (peak) plasma concentration of the drug 
λz 
h-1 
Apparent terminal-phase disposition rate constant (first-order) 
R5,ac(C24h) 
 
Accumulation ratio of 5th dose to first dose at regular administration 
for C24h 
t1/2,z 
h 
Terminal-phase elimination half-life 
tlast 
h 
Time of last measurable (positive) concentration 
tmax 
h 
Time to maximum (peak) plasma concentration 
Vz 
L 
Volume of distribution during the terminal (λz) phase 
 
 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
7 of 43 
Version 1.0 Date: 06/21/2018 
1 
Introduction 
This statistical analysis plan documents the details of the statistical analysis methodology 
to be applied in the protocol of Study 263-102-00001. 
2 
Trial Objectives 
Primary: To investigate the dose of OPC-61815 injection formulation achieving exposure 
equivalent to that for tolvaptan 15-mg tablet by 1-hour intravenous administration of 
OPC-61815 at 2, 4, 8, or 16 mg once daily or oral administration of tolvaptan tablet at 
15 mg once daily for 5 days in congestive heart failure (CHF) patients with volume 
overload despite having received diuretics other than vasopressin antagonists 
Secondary: To investigate the efficacy, pharmacokinetics, pharmacodynamics, and safety 
of OPC-61815 in comparison with tolvaptan tablet by 1-hour intravenous administration 
of OPC-61815 at 2, 4, 8, or 16 mg once daily or oral administration of tolvaptan tablet at 
15 mg once daily for 5 days in CHF patients with volume overload despite having 
received diuretics other than vasopressin antagonists. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multicenter, randomized, double-blind, active-controlled (with tolvaptan tablet), 
double-dummy, parallel group comparison trial. Fifty CHF patients with volume overload 
despite having received diuretics other than vasopressin antagonists will be randomly 
assigned to OPC-61815 injection 2 mg, 4 mg, 8 mg, or 16 mg or tolvaptan tablet 15 mg 
group (10 per group) to investigate the dose of OPC-61815 injection required to achieve 
exposure equivalent to tolvaptan 15-mg tablet. To account for withdrawals, 11 patients 
per group (total 55 patients) will start investigational medicinal product (IMP) 
administration. 
The 3-day period prior to IMP administration constitutes the run-in period. The use of 
diuretics, body weight change, and congestive symptoms are evaluated during the run-in 
period. Only the patients who meet the criteria for enrollment in the treatment period will 
be enrolled to undergo treatment. The patients will receive the IMP once a day for 5 days 
during the treatment period. No change of a diuretic dose or regimen will be allowed 
throughout the run-in period and until the end-of-trial examination on the day after final 
administration in the treatment period. End-of-trial examination will be performed on 
Day 6 (day after final administration) and post-treatment follow-up examination will be 
performed between Days 12 and 15. 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
8 of 43 
Version 1.0 Date: 06/21/2018 
This trial will be conducted using a double-dummy design to maintain blindness. 
Subjects will receive a combination of either OPC-61815 injection and placebo tablet or 
placebo injection and tolvaptan 15-mg tablet. As there will be a difference in appearance 
between the OPC-61815 solution and the placebo solution, the designated non-blinded 
staff at the trial site will prepare the double-blinded IMP. All enrolled patients will be 
admitted and remain hospitalized from the day before the start of the run-in period to the 
end of the treatment period. 
3.2 
Trial Treatments 
The investigator or subinvestigator will administer either one tolvaptan 15-mg tablet or 
placebo tablet once a day with water, immediately followed by intravenous 
administration of either OPC-61815 injection at 2 mg, 4 mg, 8 mg, or 16 mg or placebo 
for 1 hour (acceptable range: 55 to 65 minutes) according to a separate written procedure 
for IMP administration. Each dose should be administered promptly after the patient 
completes urine sampling (for daily urine volume measurement) after breakfast each day 
during the 5-day treatment period. The time of administration (start time of 
administration) on Day 2 and later should be not more than 20 minutes before or after the 
time of administration (start time of administration) on Day 1. After confirming each 
dose has been administered, the investigator or subinvestigator documents the start and 
finish time of administration (for injection) or the date and time of administration (for 
tablet) in source documents and case report form (CRF). The IMP is to be administered 
even if the patient fails to eat breakfast that day. 
3.3 
Trial Population 
Fifty-five Japanese male or female CHF patients with volume overload (lower limb 
edema, pulmonary congestion, or jugular venous distension) despite having received 
diuretics other than vasopressin antagonists, age 20 to 85 years, inclusive, will be 
enrolled in the trial (11 patients per group to start treatment). All subjects must be 
available for hospitalization from the day before the start of the run-in period to the end 
of the treatment period and also be able to swallow the tolvaptan tablet. 
3.4 
Handling of Time Points 
CRF Visit values at each time point (run-in period, treatment period, and follow-up) will 
be used in summaries (but values at the time of discontinuation will not be used in 
summaries). Unscheduled Visit values will not be used. 
Baseline and final administration time point for each variable are defined as follows. 
 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
9 of 43 
Version 1.0 Date: 06/21/2018 
Table 3.4-1 
Handling of Time Points 
Variable 
Baselinea 
Final Administration Time 
Point 
Body weight 
Before IMP administration on 
Day 1 
Day after final IMP 
administration 
Congestive symptoms 
Run-in period (final 
measurement) 
Day after final IMP 
administration 
Pulmonary congestion, 
cardiothoracic ratio 
Run-in period 
Day after final IMP 
administration 
NYHA classification  
Run-in period 
Day after final IMP 
administration 
Clinical laboratory value 
Before IMP administration on 
Day 1 
Day after final IMP 
administration 
Vital signs 
Before IMP administration on 
Day 1 
Day after final IMP 
administration 
12-lead ECG 
Run-in period 
Day after final IMP 
administration 
Serum sodium concentration, 
serum potassium concentration, 
serum osmolality, biomarker 
Before IMP administration on 
Day 1 
- 
Daily urinary output, daily fluid 
intake, daily water balance, daily 
sodium urinary excretion, daily 
potassium urinary excretion, 
urinary osmolality 
During 24 hours before start of 
IMP administration on Day 1 
- 
aWhen multiple data are collected during the run-in period, the data closest to Day 1 will be used as 
baseline. 
 
4 
Sample Size  
The primary objective of this clinical trial is to compare tolvaptan exposure in order to 
investigate the dose of OPC-61815 injection required to achieve exposure equivalent to 
tolvaptan 15-mg tablet for use in conducting phase 3 confirmatory clinical trials of OPC-
61815. The number of subjects required for this purpose was determined to be at least 10 
subjects per group (50 subjects in total) who complete blood sampling for measurement 
of plasma drug concentrations up until 24 hours postdose on Day 1. In consideration of 
the possibility of some subjects withdrawing from the trial prior to 24 hours postdose on 
Day 1, the approximate target number of subjects for the start of IMP administration is 
set at 11 subjects per group (55 subjects in total). 
5 
Statistical Analysis Sets 
5.1 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set will include all subjects treated with the IMP at least 
once and have at least one evaluable plasma drug concentration measurement (other than 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
10 of 43 
Version 1.0 Date: 06/21/2018 
Not Analyzed [NA] and Not Determined [ND]) after IMP administration. Subjects who 
withdrew from the trial or had missing data will also be included. Subjects whose entire 
data were rejected in Section 102)a) will not be included. 
5.2 
Efficacy Analysis Set 
The efficacy analysis set will include all subjects treated with the IMP at least once and 
have body weight data after IMP administration. 
5.3 
Safety Analysis Set 
The safety analysis set will include all subjects treated with the IMP at least once. 
5.4 
Pharmacodynamic Analysis Set 
The pharmacodynamic analysis set will include all subjects treated with the IMP at least 
once and have pharmacodynamic data after IMP administration. 
5.5 
Handling of Missing Data 
The last observation before the day after final IMP administration will be carried forward 
if the measurement of the day after final IMP administration for the evaluation (efficacy 
and safety) at final administration time point is missing. 
6 
Primary and Secondary Endpoints: 
6.1 
Primary Endpoint 
Tolvaptan exposure (Cmax and AUC24h on Day 1 of treatment period) 
6.2 
Secondary Endpoints 
 Pharmacokinetics 
Plasma concentrations and pharmacokinetic parameters of OPC-61815, tolvaptan, 
DM-4103, and DM-4107 
 Pharmacodynamics 
Serum concentrations of sodium and potassium, serum osmolality, biomarkers 
(plasma concentrations of arginine vasopressin [AVP] and brain natriuretic peptide 
[BNP], plasma renin activity, and serum concentrations of N-terminal pro-brain 
natriuretic peptide [NT-proBNP] and troponin), daily urine volume, daily fluid intake, 
daily fluid balance, daily urine sodium excretion, daily urine potassium excretion, and 
urine osmolality 
 Efficacy 
Body weight, congestive symptoms (lower limb edema, other edema, jugular venous 
distension, pulmonary congestion confirmed by chest X-ray, pulmonary rales, third 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
11 of 43 
Version 1.0 Date: 06/21/2018 
cardiac sound, and hepatomegaly), cardiothoracic ratio, and New York Heart 
Association (NYHA) classification 
 
7 
Disposition and Demographic Analysis 
The following will be summarized by administration group (including the entire OPC-
61815 group). 
7.1 
Subject Disposition 
For subjects from whom informed consent was obtained (screened subjects), the number 
of subjects and the numbers and percentages of randomized subjects, subjects 
administered IMP, completed subjects after IMP administration, and discontinued 
subjects after IMP administration (the denominator indicates the number of randomized 
subjects) will be summarized. For discontinued subjects after IMP administration, the 
number and percentage of subjects by reason for discontinuation will be summarized. 
For randomized subjects, the number and percentage of subjects included in each 
statistical analysis set will be summarized. 
7.2 
Demographic and Baseline Characteristics 
For the pharmacokinetic analysis set, the subject population set of the pharmacokinetic 
analysis set for which at least one primary endpoint was obtained, and safety analysis set, 
descriptive statistics (number of subjects, mean, standard deviation, minimum, median, 
and maximum, the same applies hereinafter to Chapter 9) or distributions (number of 
subjects, %, the same applies hereinafter) will be calculated according to Table 7.2-1. 
Table 7.2-1 
Demographic and Other Baseline Characteristics 
Variable 
Time Point 
Method 
Level 
Age 
Informed consent 
acquisition 
Descriptive statistics 
- 
 
Distribution 
20-29,  
30-39,  
40-49,  
50-59,  
60-69,  
70-79,  
80-85 
 
 
< 65,  
≥ 65 
Sex 
- 
Distribution 
Female,  
Male,  
Undifferentiated 
Height (cm) 
Screening 
Descriptive statistics 
- 
Body weight (kg) 
Screening 
Descriptive statistics 
- 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
12 of 43 
Version 1.0 Date: 06/21/2018 
Table 7.2-1 
Demographic and Other Baseline Characteristics 
Variable 
Time Point 
Method 
Level 
BMI (kg/m^2) 
Screening 
Descriptive statistics 
- 
Country 
- 
Distribution 
JAPAN 
Race 
- 
Distribution 
Asian 
Ethnicity 
- 
Distribution 
Not Hispanic or Latino 
Primary illness (multiple 
selection) 
• Ischemic heart disease 
• Non-ischemic 
cardiomyopathy 
• Valvular disease 
• Hypertensive heart 
disease 
• Arrhythmia 
Screening 
Distribution 
Yes,  
No, 
Unspecified 
Type of heart failure 
Screening 
Distribution 
Right Heart Failure,  
Left Heart Failure,  
Bi-ventricular Failure, 
Unspecified 
Presence of arrhythmia 
Screening 
Distribution 
Yes,  
No 
Use of Pacemaker 
Screening 
Distribution 
Yes,  
No 
Use of ICD  
Screening 
Distribution 
Yes,  
No 
Complication (multiple 
selection) 
• Hypertension 
• Angina pectoris 
• Diabetes mellitus 
• Renal impairment 
Screening 
Distribution 
Yes,  
No 
Presence of 
complication 
Screening 
Distribution 
Yes,  
No 
Presence of medical 
history 
Screening 
Distribution 
Yes,  
No 
 
7.3 
Baseline Disease Evaluation 
For the pharmacokinetic analysis set, the subject population set of the pharmacokinetic 
analysis set for which at least one primary endpoint was obtained, and safety analysis set, 
each variable at baseline will be calculated. 
Table 7.3-1 
Baseline Pathologic Evaluation 
Variable 
Method 
Level 
Cardiothoracic ratio (%)  
Descriptive statistics 
- 
NYHA classification 
Distribution 
Class I, 
Class II, 
Class III, 
Class IV 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
13 of 43 
Version 1.0 Date: 06/21/2018 
Table 7.3-1 
Baseline Pathologic Evaluation 
Variable 
Method 
Level 
Severity of lower limb edema 
Distribution 
None, 
Mild, 
Moderate, 
Severe 
Pulmonary congestion 
Distribution 
None, 
Mild, 
Moderate, 
Severe 
Presence of jugular venous 
distension 
Distribution 
Yes,  
No 
Jugular venous distension (cm) 
Descriptive statistics 
- 
Presence of hepatomegaly 
Distribution 
Yes,  
No 
Hepatomegaly (cm) 
Descriptive statistics 
- 
Pulmonary rales 
Distribution 
Yes,  
No 
Third cardiac sound  
Distribution 
Yes,  
No 
Daily urine volume 
Distribution 
< 1500 mL, 
≥ 1500 mL 
Creatinine 
Distribution 
< 2 mg/dL, 
≥ 2 mg/dL 
Plasma AVP concentration 
Distribution 
≤ 3.1 pg/mL, 
> 3.1 pg/mL 
Albumin 
Distribution 
< 3 g/dL, 
≥ 3 g/dL 
 
7.4 
Treatment Compliance 
This will be summarized for the pharmacokinetic analysis set, subject population set of 
the pharmacokinetic analysis set for which at least one primary endpoint was obtained, 
and safety analysis set. Distributions for presence or absence of discontinuation during 
IMP (injection) administration will be calculated. Distributions for presence or absence of 
days of incomplete IMP (injection) administration as well as days of missing an IMP 
(tablet) dose will also be calculated. 
7.5 
Prior and Concomitant Medications 
For the pharmacokinetic analysis set, subject population of the pharmacokinetic analysis 
set for which at least one primary endpoint was obtained, and safety analysis set, 
distributions for usage of concomitant medication on the initial IMP administration day 
will be calculated. 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
14 of 43 
Version 1.0 Date: 06/21/2018 
Table 7.5-1 
Usage of Concomitant Medication on Initial IMP 
Administration Day 
Variable 
Level 
Use of loop diuretic 
Monotherapy with loop diuretic 
Loop diuretic + other diuretic 
Dose of loop diuretic 
(Furosemide equivalenta) 
< 40 mg/day,  
≥ 40 mg/day and < 80 mg/day,  
≥ 80 mg/day 
Category of diuretic 
*Concomitant use of diuretic drugs 
other than loop diuretic, thiazide 
diuretic, and anti-aldosterone drug is 
not summarized. 
Monotherapy with loop diuretic,  
Loop diuretic + thiazide diuretic,  
Loop diuretic + anti-aldosterone drug,  
Loop diuretic + thiazide diuretic + anti-aldosterone drug  
Thiazide diuretic 
Yes, 
No 
Anti-aldosterone drug 
Yes,  
No 
Drugs for heart failure other than 
diuretics 
Yes, 
No 
Digitalis product 
Yes, 
No 
ACE inhibitor 
Yes, 
No 
Beta blocker 
Yes, 
No 
Angiotensin receptor blocker 
Yes, 
No 
aFurosemide equivalent dose of 40 mg is defined as bumetanide, 1 mg; piretanide, 6 mg; azosemide, 
60 mg; and torasemide, 8 mg. 
 
7.6 
Protocol Deviations 
For randomized subjects, distributions for presence or absence of deviations in each CRF 
classification (Dosing, Inclusion/Exclusion Criteria, Met Withdrawal Criteria But Was 
Not Withdrawn, Prohibited Concomitant Medications) will be calculated. Distributions of 
subjects with at least one deviation will also be calculated. 
8 
Efficacy Analysis 
The following analyses will be performed in the efficacy analysis set. Each analysis will 
be exploratory, and multiplicity of testing is not considered. 
8.1 
Body Weight 
Analysis of covariance using baseline weight as covariate will be performed on the 
change from baseline in body weight after final administration to calculate the least-
square mean of the difference between each OPC-61815 injection group and tolvaptan 
15-mg tablet group and its two-sided 95% confidence interval (based on the t 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
15 of 43 
Version 1.0 Date: 06/21/2018 
distribution). At each time point, descriptive statistics of measurement and change and 
percent change from baseline will be calculated for each group. 
For changes in body weight from baseline, a timecourse (mean ± standard deviation) 
from Day 1 of treatment period to follow-up will be created for each treatment group. For 
changes in body weight from baseline to the final IMP administration, a bar graph of least 
square means (two-sided 95% confidence interval) with the horizontal axis representing 
treatment groups will be created. 
8.2 
Congestive symptoms 
8.2.1 
Lower limb Edema, Other Edema, and Pulmonary Congestion 
(Chest X-ray) 
The proportion of responders (subjects who have congestive symptoms at baseline and 
have a “markedly improved” or “improved” response evaluated with reference to Table 
8.2-1) and the proportion of subjects who achieve resolution (subjects who have 
congestive symptoms at baseline and in whom the symptoms resolve after IMP 
administration) of lower limb edema and pulmonary congestion after final administration 
are calculated for each OPC-61815 injection group, together with the difference in the 
proportions between each OPC-61815 injection group and tolvaptan 15-mg group with 
the two-sided 95% confidence intervals (exact) of each difference. 
Changes in the severity of each congestive symptom at each time point (from baseline to 
after each administration and to after final administration) will be summarized for each 
group in a shift table. 
For other edema, analysis will not be performed. 
Table 8.2-1 
Response of Lower limb Edema, Other Edema, and Pulmonary 
Congestion 
 
Response 
Description 
1 
Markedly improved 
Resolution of symptom or improvement by 2 grades or more 
2 
Improved 
Improvement by 1 grade (if the symptom has resolved, an 
assessment of “markedly improved” is given instead) 
3 
No change 
No change in symptom, or absence of symptom throughout the 
trial 
4 
Worsened 
Worsening by 1 grade or more 
 
8.2.2 
Jugular Venous Distension, Hepatomegaly, and Cardiothoracic 
Ratio 
Change from baseline in jugular venous distension and cardiothoracic ratio after final 
administration will be analyzed using analysis of covariance with baseline value as 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
16 of 43 
Version 1.0 Date: 06/21/2018 
covariate to calculate the least square mean of the difference between each OPC-61815 
injection group and tolvaptan 15-mg tablet group and its two-sided 95% confidence 
intervals (based on the t distribution). Descriptive statistics of the measurements and their 
changes from baseline at each time point for jugular venous distension, hepatomegaly, 
and cardiothoracic ratio will be calculated for each group. 
8.2.3 
Pulmonary Rales and Third Cardiac Sound 
The proportion of subjects who achieve resolution of pulmonary rales and third cardiac 
sound (subjects who have the sign at baseline and who do not have the sign after IMP 
administration) will be calculated in each OPC-61815 injection group together with the 
difference in the proportion between each OPC-61815 injection group and tolvaptan 15-
mg group and its two-sided 95% confidence intervals (exact). 
Changes in the severity of pulmonary rales and third cardiac sign at each time point (from 
baseline to after each IMP administration and to after final administration) will be 
summarized for each group in a shift table. 
8.2.4 
NYHA Classification 
Changes in NYHA classification at each time point (from baseline to after each 
administration and to after final administration) will be summarized for each group in a 
shift table. 
8.3 
Subgroup Analyses 
Subgroup Analyses will not be performed in this trial. 
9 
Safety Analyses 
The following analyses will be performed for each group (including the entire OPC-
61815 group) in the safety analysis set. 
9.1 
Extent of Exposure 
Distributions of the number of subjects on each number of administration days will be 
calculated. Descriptive statistics of the number of administration days will be calculated. 
9.2 
Adverse Events  
All adverse events (AEs) will be coded by system organ class (SOC) and preferred term 
(PT) (Medical Dictionary for Regulatory Activities [MedDRA]). The incidence of the 
following events will be summarized for all events, by SOC, and by PT. 
 Treatment-emergent AEs (TEAEs) 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
17 of 43 
Version 1.0 Date: 06/21/2018 
 TEAEs by severity 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
If there are multiple occurrences of the same event in the same period in the same subject, 
the event with the highest severity will be selected. The above summaries will also be 
prepared for TEAEs potentially causally related to the IMP. 
For TEAEs, a summary table will also be created for any TEAE that occurs in more than 
2 subjects in any group. 
9.3 
Clinical Laboratory Data 
For hematology, serum chemistry (excluding PAP and TRACP-5b), and urinalysis in the 
protocol “Table 3.7.4.2-1 Clinical Laboratory Assessments” (at the central laboratory), 
the following will be summarized. 
Descriptive statistics of clinical laboratory values (excluding qualitative urinalysis other 
than pH) as well as of the changes from baseline in values at each time point and after 
final administration will be calculated. The results of qualitative urinalysis at each 
postdose time point and after final administration compared with baseline results will be 
summarized in a shift table. Each clinical laboratory value excluding qualitative 
urinalysis will be categorized into “within reference range,” “below the lower limit of 
reference range,” or “above the upper limit of reference range” using the institutional 
standard values to generate a shift table summarizing laboratory data at each postdose 
time point and after final administration compared with baseline. 
For parameters excluding qualitative urinalysis, a scatter diagram of values after the final 
administration with comparison to baseline will be created in each group. 
For presence or absence of an elevation in AST or ALT that is ≥ 3 times the upper limit 
of normal of the institutional standard values as well as an elevation in total bilirubin ≥ 2 
times the upper limit of normal of the institutional standard values at any point after IMP 
administration, the number and percentage of subjects will be calculated. 
9.4 
Vital Sign Data 
Descriptive statistics will be calculated for vital signs together with the changes from 
baseline at each time point and after final administration. 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
18 of 43 
Version 1.0 Date: 06/21/2018 
9.5 
Electrocardiogram Data 
Descriptive statistics of each 12-lead electrocardiogram (ECG) parameter and the 
changes from baseline in each parameter at each time point and after final administration 
will be calculated. 
The number and percentage of subjects who have a QTc interval (QTcB, QTcF) of “> 
450 msec”, “> 480 msec”, and “> 500 msec” at at least one postdose time point or after 
final administration will be calculated. In addition, the number and percentage of subjects 
who show a change of “> 30 msec” and “> 60 msec” in QTc interval from baseline at at 
least one postdose time point or after final administration will be calculated. The numbers 
and percentages of subjects will also be calculated at baseline and each postdose time 
point in the same manner. “Normal” and “abnormal” assessments at each postdose time 
point and after final administration compared with baseline will be summarized in a shift 
table. “Normal” and “abnormal” assessments by the trial site (investigator or 
subinvestigator) will be used instead of  the assessments by the central ECG analysis 
laboratory.  
10 
Pharmacokinetic Analyses 
This section describes the pharmacokinetics of primary and secondary endpoints.  
1) Endpoints 
a) Primary Endpoint : 
 Cmax and AUC24h of plasma tolvaptan on Day 1 of treatment period 
b) Secondary Endpoints: 
i) Plasma concentrations of OPC-61815, tolvaptan, DM-4103 and DM-4107 
ii) Plasma pharmacokinetic parameters of OPC-61815, tolvaptan, DM-4103 
and DM-4107 
 Day 1 of treatment period: Cmax
a, AUC24h
a, AUCt, AUC∞, tmax, λz, 
AUC_%Extrap, tlast, t1/2,z, CLb, CL/BWb, Vz
b, Vz/BWb, CL/Fc, CL/F/BWc 
 Day 1, Day 2, Day 3, Day 4, and Day 5 of treatment period: C24h
d 
 Day 5 of treatment period: R5,ac (C24h) 
aExcluding tolvaptan 
bCalculated only for OPC-61815 after administration of OPC-61815 injection 
cCalculated only for tolvaptan after administration of tolvaptan 15-mg tablet 
dFor calculation of descriptive statistics, C24h will be handled as plasma concentrations. 
iii) Ratio of the AUC of metabolite to that of OPC-61815e 
Day 1 of treatment period: AUC∞, AUC24h, and AUCt 
eCalculated only for the OPC-61815 injection groups 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
19 of 43 
Version 1.0 Date: 06/21/2018 
2) Handling of Data 
a) Acceptance or nonacceptance of data will be determined in accordance with 
Section 3.4 Exclusion From Pharmacokinetic Analysis of the Manual 
Standard Practice for Noncompartmental Pharmacokinetic Analysis (Version 
1.0). In other words, in this trial, data matched to the following conditions will 
not be used. 
 To calculate actual time postdose, the actual start date and time of 
administration of the active drug (start time of administration for oral tablets 
and injections may be different). 
 For each analyte, if blood sampling is conducted outside the time window for 
the analyses below, the data will be excluded from the calculation of 
descriptive statistics for plasma concentrations at that time point. However, it 
will be used for the calculation of pharmacokinetic parameters, and if the 
calculation is determined to be unsuitable, the parameter will not be adopted. 
 
Table 10-1 
Acceptable Window for Analysis of OPC-61815 
Plasma Concentration Sampling Time Point 
Acceptable Window 
Day 1 
Before start of IMP administration 
From 2 hours to immediately before 
start of IMP administration 
 
1 hour after start of IMP administration  
Within 5 minutes after end of IMP 
administrationa 
 
1.5 hours after start of IMP administration 
Specified time point ± 5 minutes 
 
2 hours after start of IMP administration 
Specified time point ± 5 minutes 
 
4 hours after start of IMP administration 
Specified time point ± 20 minutes 
 
6 hours after start of IMP administration 
Specified time point ± 30 minutes 
 
12 hours after start of IMP administration 
Specified time point ± 1 hour 
Day 2 
24 hours after start of IMP administration on Day 1 
(and before administration on Day 2)  
22 to 24 hours after start of 
administration on Day 1 
Day 3 
24 hours after start of IMP administration on Day 2 
(and before administration on Day 3)  
22 to 24 hours after start of 
administration on Day 2  
Day 4 
24 hours after start of IMP administration on Day 3 
(and before administration on Day 4)  
22 to 24 hours after start of 
administration on Day 3  
Day 5 
24 hours after start of IMP administration on Day 4 
(and before administration on Day 5)  
22 to 24 hours after start of 
administration on Day 4  
Day 6 
24 hours after start of IMP administration on Day 5 
22 to 24 hours after start of 
administration on Day 5 
aFor the tolvaptan 15-mg tablet group, within 1 hour ± 5 minutes after start of IMP administration 
(= after end of IMP administration) 
 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
20 of 43 
Version 1.0 Date: 06/21/2018 
Table 10-2 
Acceptable Window for Analysis of Analytes other than 
OPC-61815 
Plasma Concentration Sampling Time Point 
Acceptable Window 
Day 1 
Before start of IMP administration 
From 2 hours to immediately before 
start of IMP administration 
 
1 hour after start of IMP administration 
Within 6 minutes after end of IMP 
administrationa 
 
1.5 hours after start of IMP administration 
Specified time point ± 10 minutes 
 
2 hours after start of IMP administration 
Specified time point ± 10 minutes 
 
4 hours after start of IMP administration 
Specified time point ± 35 minutes 
 
6 hours after start of IMP administration 
Specified time point ± 40 minutes 
 
12 hours after start of IMP administration 
Specified time point ± 1 hour 
Day 2 
24 hours after start of IMP administration on Day 1 
(and before administration on Day 2)  
22 to 24 hours after start of IMP 
administration on Day 1 
Day 3 
24 hours after start of IMP administration on Day 2 
(and before administration on Day 3)  
22 to 24 hours after start of IMP 
administration on Day 2 
Day 4 
24 hours after start of IMP administration on Day 3 
(and before administration on Day 4)  
22 to 24 hours after start of IMP 
administration on Day 3 
Day 5 
24 hours after start of IMP administration on Day 4 
(and before administration on Day 5) 
22 to 24 hours after start of IMP 
administration on Day 4 
Day 6 
24 hours after start of IMP administration on Day 5 
22 to 24 hours after start of IMP 
administration on Day 5 
aFor the tolvaptan 15-mg tablet group, within 1 hour ± 6 minutes after start of IMP administration 
(= after end of IMP administration) 
 
 If a subject in the tolvaptan 15-mg tablet group experiences vomiting within 8 
hours (twice the median tmax [4 hours1]) after IMP administration, none of the 
postdose plasma concentration data on that day will be used for the calculation 
of descriptive statistics. Of the parameters calculated with data including 
plasma concentrations excluded from descriptive statistics, the parameters 
determined to be unsuitable for the calculations will not be adopted. 
 None of the plasma concentrations after use of drugs or food (see Protocol 
Version 2 Table 4.1-3) which may inhibit or induce CYP3A4 activity will be 
used (This also applies to plasma concentrations of the following day or later). 
Of the parameters calculated with data including plasma concentrations 
excluded from descriptive statistics, the parameters determined to be 
unsuitable for the calculations will not be adopted. 
 If the administration method specified in the protocol (see below) is not 
applied to administer the IMP, the instructions listed below will be followed. 
a) Tolvaptan 15-mg tablet group: One tablet is taken with water once daily. 
- For the tolvaptan 15-mg tablet group, in the event of overdosing or missing a 
dose, plasma concentration at predose on that day will be used, but none of the 
plasma concentrations after that time point (including the plasma 
concentrations after administration on the following day or later) will be used 
for the calculation of descriptive statistics. 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
21 of 43 
Version 1.0 Date: 06/21/2018 
b) OPC-61815 injection 2 mg, 4 mg, 8 mg, and 16 mg groups: The assigned 
dose is administered intravenously for 1 hour (acceptable range: 55 to 65 
minutes) once daily. 
- For OPC-61815 injection 2 mg, 4 mg, 8 mg, and 16 mg groups, in the event 
of insufficient dose administration, overdosing, or missing a dose, plasma 
concentration at predose on that day will be used, but the plasma 
concentrations after that time point (including the plasma concentrations after 
administration on the following day or later) will not be used for the 
calculation of descriptive statistics. In the event of full dose administration but 
outside the acceptable window because of interruption, etc or full dose 
administration with an unknown administration time, plasma concentrations 
after administration on that day will not be used (plasma concentrations at 
predose on the following day and after administration on the following day or 
later will be used). 
Of the parameters calculated with data including plasma concentrations 
excluded from descriptive statistics, the parameters determined to be 
unsuitable for the calculations will not be adopted. 
 For each analyte, if a quantitative value is obtained at predose on Day 1, and 
the value exceeds 5 % or more of the highest value of the period between 1 
hour and 24 hours after administration on Day 1, the plasma concentrations 
for that analyte at predose and thereafter will be excluded from the calculation 
of descriptive statistics. Parameters of the analyte with all of the plasma 
concentrations excluded from the calculation of descriptive statistics will not 
be adopted. 
b) Plasma concentrations below lower limit of quantitation that occur prior to 
and after the first measurable concentration will be imputed to 0 (ng/mL) and 
missing. Lower limit of quantitation of each analyte is listed in Appendix 3. 
c) Concentrations reported as Not Analyzed (NA) or Not Determined (ND) are 
regarded as missing values. 
3) Statistical Analysis Method 
a) Primary Endpoint 
i) For primary endpoint, analysis will be performed for the subject 
population set of the pharmacokinetic analysis set for which at least one 
primary endpoint was obtained. 
ii) For “1)a) Primary Endpoint,” descriptive statistics will be calculated for 
each parameter by treatment group. 
iii) For “1)a) Primary Endpoint,” logarithm converted value (natural 
logarithm) will be used to calculate the mean difference (each OPC-61815 
injection group − tolvaptan 15-mg tablet group) and the 95% confidence 
interval of the difference. 
b) Secondary Endpoints 
i) For secondary endpoints, analyses will be conducted for the 
pharmacokinetic analysis set. 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
22 of 43 
Version 1.0 Date: 06/21/2018 
ii) For “1)b) Secondary Endpoints i),” descriptive statistics at each blood 
sampling point will be calculated by administration date, analyte, and 
treatment group. 
iii) For “1)b) Secondary Endpoints ii)” (excluding λz, λz(lower), λz(upper), 
λz(point) and λz(Rsq)), descriptive statistics of each parameter will be 
calculated by administration date, analyte, and treatment group. 
iv) For “1)b) Secondary Endpoints iii),” descriptive statistics of each 
parameter will be calculated by analyte and treatment group. 
c) Descriptive Statistics 
Descriptive statistics to be calculated for plasma drug concentration will be 
number of analyzed subjects, number of subjects for which concentrations data 
were obtained (excluding missing data or unadopted data), arithmetic mean, 
standard deviation, coefficient of variation, minimum, median, and maximum. 
However, descriptive statistics will be calculated only at the time point when the 
number of subjects for which data were obtained (excluding missing data or 
unadopted data) exceeds half of the number of analyzed subjects in each group. 
For variables other than plasma drug concentration, descriptive statistics to be 
calculated will be number of analyzed subjects, number of subjects for which data 
were obtained (excluding incalculable data or unadopted data), arithmetic mean, 
standard deviation, coefficient of variation, geometric mean, minimum, median, 
and maximum. However, descriptive statistics will be calculated only when the 
number of subjects for which data were obtained (excluding Not Determined 
(ND) or unadopted data) exceeds half of the number of analyzed subjects in each 
group. 
11 
Pharmacodynamic Analyses 
Analyses will be performed in the pharmacodynamic analysis set. 
For each of the endpoints listed below, descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median, and maximum) of the measurement and the 
change from baseline will be calculated for each group at each time point. For daily urine 
volume, daily fluid intake, and daily fluid balance after IMP administration on Day 1 and 
after IMP administration on Day 5, the difference (each OPC-61815 injection group − 
tolvaptan 15-mg tablet) in mean change from baseline and its 95% confidence interval 
(based on t distribution) will be calculated. 
For daily urine output, a transition chart of measurements (mean ± standard deviation) 
from the run-in period to Day 5 will be created in each group. For changes from baseline 
after IMP administration on Day 1 and after IMP administration on Day 5, a bar graph of 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
23 of 43 
Version 1.0 Date: 06/21/2018 
the mean (two-sided 95% confidence interval) with the horizontal axis representing 
treatment groups will also be created. 
 Serum sodium concentration, serum potassium concentration (at the central 
laboratory)  
 Serum osmolality  
 Biomarkers (plasma AVP concentration, plasma BNP concentration, plasma renin 
activity, serum NT-proBNP, serum troponin concentration) 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Daily urine sodium excretion 
 Daily urine potassium excretion 
 Urine osmolality 
 
12 
Pharmacogenomic Analyses 
No pharmacogenomic analysis will be performed in this trial. 
13 
Interim Analysis 
No interim analysis will be performed in this trial. 
14 Changes in the Planned Analyses 
 For further clarification, handling of discontinued subjects and subjects with missing 
data was added to Protocol 6.1.1. Pharmacokinetic Analysis Set. 
 For erroneous entry, “V” described in Protocol 6.1.2 (1) (b) Secondary endpoints 2) 
was changed to “Vz.” Since “Vz/BW” was erroneously omitted, it was added. 
 For omission in entry, an explanatory note on treating C24h as the plasma 
concentration for the calculation of descriptive statistics was added. 
 For omission in entry, a note considering IMP administration methods in addition to 
the manual on data handling was added. 
 In Protocol 6.1.2 (3) Analytical Method 2), the analysis set for primary endpoints was 
added for clarification. 
 In Protocol 6.1.2 (3) Analytical Method 2), the calculation method in “6.1.2 (1) (b) 
Secondary endpoints 3)” was added because it was erroneously omitted. 
 For erroneous entry, “after final administration” described in Protocol 6.2 
Pharmacodynamics was changed to “after administration on Day 5.” 
 For erroneous entry, “Analysis of covariance using baseline weight as covariate will 
be performed on the change (absolute change and percent change)” described in 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
24 of 43 
Version 1.0 Date: 06/21/2018 
Protocol 7.4.1 Body Weight was changed to “Analysis of covariance using baseline 
weight as covariate will be performed on the change.” 
 Because the evaluation of multiple sections all together is difficult, it was decided not 
to summarize for other edema described in Protocol 7.4.2.1. 
 Because of the low number of applicable subjects, hepatomegaly described in 
Protocol 7.4.2.2. was eliminated from the list for analysis of covariance 
 
15 
References 
1 
Package insert for Samsca tablet (tolvaptan tablet) 7.5 mg, 15 mg, 30 mg 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
25 of 43 
Version 1.0 Date: 06/21/2018 
Appendix 1 
List of Tables and Figures 
 
CT-1 
Subject Disposition (Screened Subjects) 
CT-2.1 
Reasons for Discontinuation (Randomized Subjects) 
CT-2.2 
Protocol Deviations (Randomized Subjects) 
CT-3.1.1 
Demographic and Baseline Characteristics (Safety Analysis Set) 
CT-3.1.2 
Demographic and Baseline Characteristics (Pharmacokinetics Analysis 
Set) 
CT-3.1.3 
Demographic and Baseline Characteristics (Pharmacokinetics Analysis 
Set (2)) 
CT-3.2.1 
Medical History (1) (Safety Analysis Set) 
CT-3.2.2 
Medical History (1) (Pharmacokinetics Analysis Set) 
CT-3.2.3 
Medical History (1) (Pharmacokinetics Analysis Set (2)) 
CT-3.2.4 
Medical History (2) (Safety Analysis Set) 
CT-3.2.5 
Medical History (2) (Pharmacokinetics Analysis Set) 
CT-3.2.6 
Medical History (2) (Pharmacokinetics Analysis Set (2)) 
CT-3.3.1 
Concomitant Medications Used on the First Day of Trial Drug 
Administration (1) (Safety Analysis Set) 
CT-3.3.2 
Concomitant Medications Used on the First Day of Trial Drug 
Administration (1) (Pharmacokinetics Analysis Set) 
CT-3.3.3 
Concomitant Medications Used on the First Day of Trial Drug 
Administration (1) (Pharmacokinetics Analysis Set (2)) 
CT-3.3.4 
Concomitant Medications Used on the First Day of Trial Drug 
Administration (2) (Safety Analysis Set) 
CT-3.3.5 
Concomitant Medications Used on the First Day of Trial Drug 
Administration (2) (Pharmacokinetics Analysis Set) 
CT-3.3.6 
Concomitant Medications Used on the First Day of Trial Drug 
Administration (2) (Pharmacokinetics Analysis Set (2)) 
CT-3.4.1 
Baseline Disease Evaluation (Safety Analysis Set) 
CT-3.4.2 
Baseline Disease Evaluation (Pharmacokinetics Analysis Set) 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
26 of 43 
Version 1.0 Date: 06/21/2018 
CT-3.4.3 
Baseline Disease Evaluation (Pharmacokinetics Analysis Set (2)) 
CT-5.1 
Analysis of Covariance for Change from Baseline in Body Weight at Last 
Visit (Efficacy Analysis Set) 
CT-5.2 
Descriptive Statistics for Change from Baseline in Body Weight (Efficacy 
Analysis Set) 
CT-5.3 
Descriptive Statistics for Change Rate from Baseline in Body Weight 
(Efficacy Analysis Set) 
CT-6.1.1 
Improvement Rate for Lower Limb Edema and Pulmonary Congestion at 
Last Visit (Efficacy Analysis Set) 
CT-6.1.2 
Disappearance Rate for Lower Limb Edema and Pulmonary Congestion 
at Last Visit (Efficacy Analysis Set) 
CT-6.2 
Shift Table for Lower Limb Edema (Efficacy Analysis Set) 
CT-6.3 
Shift Table for Pulmonary Congestion (Efficacy Analysis Set) 
CT-6.4 
Analysis of Covariance for Change from Baseline in Juglar Venous 
Distension at Last Visit (Efficacy Analysis Set) 
CT-6.5 
Descriptive Statistics for Juglar Venous Distension (cm) (Efficacy 
Analysis Set) 
CT-6.6 
Analysis of Covariance for Change from Baseline in Cardiothoracic Ratio 
at Last Visit (Efficacy Analysis Set) 
CT-6.7 
Descriptive Statistics for Cardiothoracic Ratio (%) (Efficacy Analysis 
Set) 
CT-6.8 
Disappearance Rate for Pulmonary rales and Third Cardiac Sound at Last 
Visit (Efficacy Analysis Set) 
CT-6.9 
Shift Table for Pulmonary rales (Efficacy Analysis Set) 
CT-6.10 
Shift Table for Third Cardiac Sound (Efficacy Analysis Set) 
CT-6.11 
Shift Table for NYHA Classification (Efficacy Analysis Set) 
CT-7.1 
Extent of Exposure to Investigational Medicinal Product (Safety Analysis 
Set) 
CT-7.2.1 
Treatment Compliance (Safety Analysis Set) 
CT-7.2.2 
Treatment Compliance (Pharmacokinetics Analysis Set) 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
27 of 43 
Version 1.0 Date: 06/21/2018 
CT-7.2.3 
Treatment Compliance (Pharmacokinetics Analysis Set (2)) 
CT-8.1  
Overall Summary of Adverse Events (Safety Analysis Set) 
CT-8.2  
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.3 
Incidences of Potentially Drug-related Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set) 
CT-8.4 
Incidences of Treatment-emergent Adverse Events by Severity by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.5 
Incidences of Potentially Drug-related Treatment-emergent Adverse 
Events by Severity by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-8.6 
Incidences of Treatment-emergent Adverse Events Greater Than or Equal 
to 2 Subjects in Any Treatment Group by MedDRA System Organ Class 
and Preferred Term (Safety Analysis Set) 
CT-8.7 
Incidences of Potentially Drug-related Treatment-emergent Adverse 
Events Greater Than or Equal to 2 Subjects in Any Treatment Group by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set) 
CT-9.1 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set) 
CT-9.2 
Incidences of Potentially Drug-related Treatment-emergent Adverse 
Events with an outcome of death by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-9.3 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term (Safety Analysis Set) 
CT-9.4 
Incidences of Potentially Drug-related Serious Treatment-emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-9.5 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set) 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
28 of 43 
Version 1.0 Date: 06/21/2018 
CT-9.6 
Incidences of Potentially Drug-related Treatment-emergent Adverse 
Events Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-9.7 
Listing of Deaths (Safety Analysis Set) 
CT-9.8 
Listing of Subject With Serious Adverse Events Other Than Death 
(Safety Analysis Set) 
CT-9.9 
Listing of Subject With Adverse Events Leading to Discontinuation of 
Investigational Medicinal Product Administration (Safety Analysis Set) 
CT-10.1.1 
Mean Change from Baseline in Clinical Laboratory Test Results (Serum 
Chemistry) (Safety Analysis Set) 
CT-10.1.2 
Mean Change from Baseline in Clinical Laboratory Test Results 
(Hematology) (Safety Analysis Set) 
CT-10.1.3 
Mean Change from Baseline in Clinical Laboratory Test Results 
(Urinalysis) (Safety Analysis Set) 
CT-10.2 
Shift Tables of Clinical Laboratory Test Results (Qualitative Urinalysis) 
(Safety Analysis Set) 
CT-10.3.1 
Shift Tables of Clinical Laboratory Test Results (Serum Chemistry) 
(Safety Analysis Set) 
CT-10.3.2 
Shift Tables of Clinical Laboratory Test Results (NA, K) (Safety Analysis 
Set) 
CT-10.3.3 
Shift Tables of Clinical Laboratory Test Results (Hematology) (Safety 
Analysis Set) 
CT-10.3.4 
Shift Tables of Clinical Laboratory Test Results (Urinalysis) (Safety 
Analysis Set) 
CT-10.4.1 
Listing of Abnormal Laboratory Findings (Safety Analysis Set) 
CT-10.4.2 
Listing of Abnormal Laboratory Findings Potential Drug-Induced Liver 
Injury (Randomized Subjects) 
CT-10.5 
Incidence of Potential Drug-Induced Liver Injury (Safety Analysis Set) 
CT-11 
Mean Change from Baseline in Vital Signs (Safety Analysis Set) 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
29 of 43 
Version 1.0 Date: 06/21/2018 
CT-12.1 
Mean Change from Baseline in Electrocardiogram Results (Safety 
Analysis Set) 
CT-12.2 
Shift Table of 12-Lead ECG Findings (Normal/Abnormal Assessments) 
(Safety Analysis Set) 
CT-12.3.1 
Incidence of Categorical Changes in Electrocardiogram Results in All 
Visits (Safety Analysis Set) 
CT-12.3.2 
Incidence of Categorical Changes in Electrocardiogram Results at 
Baseline (Run-in Period) (Safety Analysis Set) 
CT-12.3.3 
Incidence of Categorical Changes in Electrocardiogram Results on Day 1 
(Safety Analysis Set) 
CT-12.3.4 
Incidence of Categorical Changes in Electrocardiogram Results on Day 3 
(Safety Analysis Set) 
CT-12.3.5 
Incidence of Categorical Changes in Electrocardiogram Results on Day 6 
(Safety Analysis Set) 
CT-12.3.6 
Incidence of Categorical Changes in Electrocardiogram Results on Last 
Visit (Safety Analysis Set) 
PDT-1 
Descriptive Statistics for Serum Sodium Concentration (mEq/L) 
(Pharmacodynamics Analysis Set) 
PDT-2 
Descriptive Statistics for Serum Potassium Concentration (mEq/L) 
(Pharmacodynamics Analysis Set) 
PDT-3 
Descriptive Statistics for Serum Osmolality (mOsm/kg) 
(Pharmacodynamics Analysis Set) 
PDT-4 
Descriptive Statistics for Plasma BNP Concentration (pg/mL) 
(Pharmacodynamics Analysis Set) 
PDT-5 
Descriptive Statistics for Serum pro BNP Concentration (pg/mL) 
(Pharmacodynamics Analysis Set) 
PDT-6 
Descriptive Statistics for Serum Troponin Concentration (pg/mL) 
(Pharmacodynamics Analysis Set) 
PDT-7 
Descriptive Statistics for Plasma AVP Concentration (pg/mL) 
(Pharmacodynamics Analysis Set) 
PDT-8 
Descriptive Statistics for Plasma Renin Activity (ng/mL/hr) 
(Pharmacodynamics Analysis Set) 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
30 of 43 
Version 1.0 Date: 06/21/2018 
PDT-9 
Descriptive Statistics for Daily Urine Volume (mL) (Pharmacodynamics 
Analysis Set) 
PDT-10 
Descriptive Statistics for Daily Fluid Intake (mL) (Pharmacodynamics 
Analysis Set) 
PDT-11 
Descriptive Statistics for Daily Fluid Balance (mL) (Pharmacodynamics 
Analysis Set) 
PDT-12 
Descriptive Statistics for Daily Urine Excretion of Sodium (mEq) 
(Pharmacodynamics Analysis Set) 
PDT-13 
Descriptive Statistics for Daily Urine Excretion of Potassium (mEq) 
(Pharmacodynamics Analysis Set) 
PDT-14 
Descriptive Statistics for Urine Osmolality (mOsm/kg) 
(Pharmacodynamics Analysis Set) 
CF-1 
Transition Diagram for Body Weight (Efficacy Analysis Set) 
CF-2 
Bar Graph for Body Weight (Efficacy Analysis Set) 
CF-3 
Scatter Plot for Clinical Laboratory Tests (Safety Analysis Set) 
CF-4 
Transition Diagram for Daily Urine Volume (Pharmacodynamics 
Analysis Set) 
CF-5 
Bar Graph for Daily Urine Volume (Pharmacodynamics Analysis Set) 
PKT-1.1.1.1 
Individual and Summary of OPC-61815 Plasma Concentration Following 
Single Intravenous Administration of OPC-61815 
PKT-1.1.1.2 
Individual and Summary of OPC-41061 Plasma Concentration Following 
Single Intravenous Administration of OPC-61815 
PKT-1.1.1.3 
Individual and Summary of DM-4103 Plasma Concentration Following 
Single Intravenous Administration of OPC-61815 
PKT-1.1.1.4 
Individual and Summary of DM-4107 Plasma Concentration Following 
Single Intravenous Administration of OPC-61815 
PKT-1.1.2.1 
Individual and Summary of OPC-61815 Plasma Pharmacokinetic 
Parameters Following Single Intravenous Administration of OPC-61815 
PKT-1.1.2.2 
Individual and Summary of OPC-41061 Plasma Pharmacokinetic 
Parameters Following Single Intravenous Administration of OPC-61815 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
31 of 43 
Version 1.0 Date: 06/21/2018 
PKT-1.1.2.3 
Individual and Summary of DM-4103 Plasma Pharmacokinetic 
Parameters Following Single Intravenous Administration of OPC-61815 
PKT-1.1.2.4 
Individual and Summary of DM-4107 Plasma Pharmacokinetic 
Parameters Following Single Intravenous Administration of OPC-61815 
PKT-1.1.3.1 
Individual and Summary of OPC-61815 Plasma Concentration Following 
Multiple Intravenous Administration of OPC-61815 
PKT-1.1.3.2 
Individual and Summary of OPC-41061 Plasma Concentration Following 
Multiple Intravenous Administration of OPC-61815 
PKT-1.1.3.3 
Individual and Summary of DM-4103 Plasma Concentration Following 
Multiple Intravenous Administration of OPC-61815 
PKT-1.1.3.4 
Individual and Summary of DM-4107 Plasma Concentration Following 
Multiple Intravenous Administration of OPC-61815 
PKT-1.1.4.1 
Individual and Summary of OPC-61815 Plasma Trough Concentration 
Following Intravenous Administration of OPC-61815 
PKT-1.1.4.2 
Individual and Summary of OPC-41061 Plasma Trough Concentration 
Following Intravenous Administration of OPC-61815 
PKT-1.1.4.3 
Individual and Summary of DM-4103 Plasma Trough Concentration 
Following Intravenous Administration of OPC-61815 
PKT-1.1.4.4 
Individual and Summary of DM-4107 Plasma Trough Concentration 
Following Intravenous Administration of OPC-61815 
PKT-1.1.6.1 
Individual and Summary of OPC-61815 Plasma Accumulation 
Parameters Following Multiple Intravenous Administration of OPC-
61815 
PKT-1.1.6.2 
Individual and Summary of OPC-41061 Plasma Accumulation 
Parameters Following Multiple Intravenous Administration of OPC-
61815 
PKT-1.1.6.3 
Individual and Summary of DM-4103 Plasma Accumulation Parameters 
Following Multiple Intravenous Administration of OPC-61815 
PKT-1.1.6.4 
Individual and Summary of DM-4107 Plasma Accumulation Parameters 
Following Multiple Intravenous Administration of OPC-61815 
PKT-1.2.1.1 
Individual and Summary of OPC-41061 Plasma Concentration Following 
Single Oral Administration of OPC-41061 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
32 of 43 
Version 1.0 Date: 06/21/2018 
PKT-1.2.1.2 
Individual and Summary of OPC-61815 Plasma Concentration Following 
Single Oral Administration of OPC-41061 
PKT-1.2.1.3 
Individual and Summary of DM-4103 Plasma Concentration Following 
Single Oral Administration of OPC-41061 
PKT-1.2.1.4 
Individual and Summary of DM-4107 Plasma Concentration Following 
Single Oral Administration of OPC-41061 
PKT-1.2.2.1 
Individual and Summary of OPC-41061 Plasma Pharmacokinetic 
Parameters Following Single Oral Administration of OPC-41061 
PKT-1.2.2.2 
Individual and Summary of OPC-61815 Plasma Pharmacokinetic 
Parameters Following Single Oral Administration of OPC-41061 
PKT-1.2.2.3 
Individual and Summary of DM-4103 Plasma Pharmacokinetic 
Parameters Following Single Oral Administration of OPC-41061 
PKT-1.2.2.4 
Individual and Summary of DM-4107 Plasma Pharmacokinetic 
Parameters Following Single Oral Administration of OPC-41061 
PKT-1.2.3.1 
Individual and Summary of OPC-41061 Plasma Concentration Following 
Multiple Intravenous Administration of OPC-41061 
PKT-1.2.3.2 
Individual and Summary of OPC-61815 Plasma Concentration Following 
Multiple Intravenous Administration of OPC-41061 
PKT-1.2.3.3 
Individual and Summary of DM-4103 Plasma Concentration Following 
Multiple Intravenous Administration of OPC-41061 
PKT-1.2.3.4 
Individual and Summary of DM-4107 Plasma Concentration Following 
Multiple Intravenous Administration of OPC-41061 
PKT-1.2.4.1 
Individual and Summary of OPC-41061 Plasma Trough Concentration 
Following Oral Administration of OPC-41061 
PKT-1.2.4.2 
Individual and Summary of OPC-61815 Plasma Trough Concentration 
Following Oral Administration of OPC-41061 
PKT-1.2.4.3 
Individual and Summary of DM-4103 Plasma Trough Concentration 
Following Oral Administration of OPC-41061 
PKT-1.2.4.4 
Individual and Summary of DM-4107 Plasma Trough Concentration 
Following Oral Administration of OPC-41061 
PKT-1.2.6.1 
Individual and Summary of OPC-41061 Plasma Accumulation 
Parameters Following Multiple Oral Administration of OPC-41061 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
33 of 43 
Version 1.0 Date: 06/21/2018 
PKT-1.2.6.2 
Individual and Summary of OPC-61815 Plasma Accumulation 
Parameters Following Multiple Oral Administration of OPC-41061 
PKT-1.2.6.3 
Individual and Summary of DM-4103 Plasma Accumulation Parameters 
Following Multiple Oral Administration of OPC-41061 
PKT-1.2.6.4 
Individual and Summary of DM-4107 Plasma Accumulation Parameters 
Following Multiple Oral Administration of OPC-41061 
PKT-1.3.1.1 
Comparison of OPC-41061 Exposure (Cmax and AUC24h) Between 
Single Intravenous Administration of OPC-61815 and Single Oral 
Administration of OPC-41061 
PKF-1.1.1.1 
Mean OPC-61815 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.1.2 
Mean OPC-41061 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.1.3 
Mean DM-4103 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.1.4 
Mean DM-4107 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.2.1 
Median OPC-61815 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.2.2 
Median OPC-41061 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.2.3 
Median DM-4103 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.2.4 
Median DM-4107 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.3.1 
OPC-61815 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.3.2 
OPC-41061 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.3.3 
DM-4103 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
34 of 43 
Version 1.0 Date: 06/21/2018 
PKF-1.1.3.4 
DM-4107 Plasma Concentrations Following Single Intravenous 
Administration of OPC-61815 
PKF-1.1.4.1 
Mean OPC-61815 Plasma Concentrations Following Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.4.2 
Mean OPC-41061 Plasma Concentrations Following Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.4.3 
Mean DM-4103 Plasma Concentrations Following Multiple Intravenous 
Administration of OPC-61815 
PKF-1.1.4.4 
Mean DM-4107 Plasma Concentrations Following Multiple Intravenous 
Administration of OPC-61815 
PKF-1.1.5.1 
Median OPC-61815 Plasma Concentrations Following Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.5.2 
Median OPC-41061 Plasma Concentrations Following Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.5.3 
Median DM-4103 Plasma Concentrations Following Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.5.4 
Median DM-4107 Plasma Concentrations Following Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.6.1 
Mean OPC-61815 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 
PKF-1.1.6.2 
Mean OPC-41061 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 
PKF-1.1.6.3 
Mean DM-4103 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 
PKF-1.1.6.4 
Mean DM-4107 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 
PKF-1.1.7.1 
Median OPC-61815 Plasma Trough Concentrations Following 
Intravenous Administration of OPC-61815 
PKF-1.1.7.2 
Median OPC-41061 Plasma Trough Concentrations Following 
Intravenous Administration of OPC-61815 
PKF-1.1.7.3 
Median DM-4103 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
35 of 43 
Version 1.0 Date: 06/21/2018 
PKF-1.1.7.4 
Median DM-4107 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 
PKF-1.1.8.1 
Mean OPC-61815 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.8.2 
Mean OPC-41061 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.8.3 
Mean DM-4103 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.8.4 
Mean DM-4107 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.9.1 
Median OPC-61815 Plasma Concentrations Following Single and 
Multiple Intravenous Administration of OPC-61815 
PKF-1.1.9.2 
Median OPC-41061 Plasma Concentrations Following Single and 
Multiple Intravenous Administration of OPC-61815 
PKF-1.1.9.3 
Median DM-4103 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.9.4 
Median DM-4107 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.10.1 OPC-61815 Plasma Concentrations Following Multiple Intravenous 
Administration of OPC-61815 
PKF-1.1.10.2 OPC-41061 Plasma Concentrations Following Multiple Intravenous 
Administration of OPC-61815 
PKF-1.1.10.3 DM-4103 Plasma Concentrations Following Multiple Intravenous 
Administration of OPC-61815 
PKF-1.1.10.4 DM-4107 Plasma Concentrations Following Multiple Intravenous 
Administration of OPC-61815 
PKF-1.1.11.1 OPC-61815 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 
PKF-1.1.11.2 OPC-41061 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 
PKF-1.1.11.3 DM-4103 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
36 of 43 
Version 1.0 Date: 06/21/2018 
PKF-1.1.11.4 DM-4107 Plasma Trough Concentrations Following Intravenous 
Administration of OPC-61815 
PKF-1.1.12.1 OPC-61815 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.12.2 OPC-41061 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.12.3 DM-4103 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.1.12.4 DM-4107 Plasma Concentrations Following Single and Multiple 
Intravenous Administration of OPC-61815 
PKF-1.2.1.1 
Mean OPC-41061 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.1.2 
Mean OPC-61815 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.1.3 
Mean DM-4103 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.1.4 
Mean DM-4107 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.2.1 
Median OPC-41061 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.2.2 
Median OPC-61815 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.2.3 
Median DM-4103 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.2.4 
Median DM-4107 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.3.1 
OPC-41061 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.3.2 
OPC-61815 Plasma Concentrations Following Single Oral 
Administration of OPC-41061 
PKF-1.2.3.3 
DM-4103 Plasma Concentrations Following Single Oral Administration 
of OPC-41061 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
37 of 43 
Version 1.0 Date: 06/21/2018 
PKF-1.2.3.4 
DM-4107 Plasma Concentrations Following Single Oral Administration 
of OPC-41061 
PKF-1.2.4.1 
Mean OPC-41061 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.4.2 
Mean OPC-61815 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.4.3 
Mean DM-4103 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.4.4 
Mean DM-4107 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.5.1 
Median OPC-41061 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.5.2 
Median OPC-61815 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.5.3 
Median DM-4103 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.5.4 
Median DM-4107 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.6.1 
Mean OPC-41061 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 
PKF-1.2.6.2 
Mean 61815 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 
PKF-1.2.6.3 
Mean DM-4103 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 
PKF-1.2.6.4 
Mean DM-4107 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 
PKF-1.2.7.1 
Median OPC-41061 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 
PKF-1.2.7.2 
Median 61815 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 
PKF-1.2.7.3 
Median DM-4103 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
38 of 43 
Version 1.0 Date: 06/21/2018 
PKF-1.2.7.4 
Median DM-4107 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 
PKF-1.2.8.1 
Mean OPC-41061 Plasma Concentrations Following Single and Multiple 
Oral Administration of OPC-41061 
PKF-1.2.8.2 
Mean OPC-61815 Plasma Concentrations Following Single and Multiple 
Oral Administration of OPC-41061 
PKF-1.2.8.3 
Mean DM-4103 Plasma Concentrations Following Single and Multiple 
Oral Administration of OPC-41061 
PKF-1.2.8.4 
Mean DM-4107 Plasma Concentrations Following Single and Multiple 
Oral Administration of OPC-41061 
PKF-1.2.9.1 
Median OPC-41061 Plasma Concentrations Following Single and 
Multiple Oral Administration of OPC-41061 
PKF-1.2.9.2 
Median OPC-61815 Plasma Concentrations Following Single and 
Multiple Oral Administration of OPC-41061 
PKF-1.2.9.3 
Median DM-4103 Plasma Concentrations Following Single and Multiple 
Oral Administration of OPC-41061 
PKF-1.2.9.4 
Median DM-4107 Plasma Concentrations Following Single and Multiple 
Oral Administration of OPC-41061 
PKF-1.2.10.1 OPC-41061 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.10.2 OPC-61815 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.10.3 DM-4103 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.10.4 DM-4107 Plasma Concentrations Following Multiple Oral 
Administration of OPC-41061 
PKF-1.2.11.1 OPC-41061 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 
PKF-1.2.11.2 OPC-61815 Plasma Trough Concentrations Following Oral 
Administration of OPC-41061 
PKF-1.2.11.3 DM-4103 Plasma Trough Concentrations Following Oral Administration 
of OPC-41061 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
39 of 43 
Version 1.0 Date: 06/21/2018 
PKF-1.2.11.4 DM-4107 Plasma Trough Concentrations Following Oral Administration 
of OPC-41061 
PKF-1.2.12.1 OPC-41061 Plasma Concentrations Following Single and Multiple Oral 
Administration of OPC-41061 
PKF-1.2.12.2 OPC-61815 Plasma Concentrations Following Single and Multiple Oral 
Administration of OPC-41061 
PKF-1.2.12.3 DM-4103 Plasma Concentrations Following Single and Multiple Oral 
Administration of OPC-41061 
PKF-1.2.12.4 DM-4107 Plasma Concentrations Following Single and Multiple Oral 
Administration of OPC-41061 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
40 of 43 
Version 1.0 Date: 06/21/2018 
Appendix 2 
List of Subject Data 
 
AE-1 
Adverse Events (Randomized Subjects) 
AE-2 
Adverse Events Observed Before Start of Investigational Medicinal 
Product Administration (Randomized Subjects) 
DEMOG-1 
Demographic and Baseline Characteristics (Randomized Subjects) 
DREAS-1 
Discontinued Subjects and Reason for Discontinuation (Randomized 
Subjects) 
LAB-1.1 
Laboratory Test Results - Serum Chemistry (Randomized Subjects) 
LAB-1.2 
Laboratory Test Results - Serum Chemistry (from ADaM) (Randomized 
Subjects) 
LAB-2.1 
Laboratory Test Results - Hematology (Randomized Subjects) 
LAB-2.2 
Laboratory Test Results - Hematology (from ADaM) (Randomized 
Subjects) 
LAB-3.1 
Laboratory Test Results - Urinalysis (Randomized Subjects) 
LAB-3.2 
Laboratory Test Results - Urinalysis (from ADaM) (Randomized 
Subjects) 
LAB-4 
Laboratory Test Results - Serum Sodium Trial Site (Randomized 
Subjects) 
PDEV-1 
Protocol Deviations (Randomized Subjects) 
SMED-1 
Investigational Medicinal Product Compliance Injection (Randomized 
Subjects) 
SMED-2 
Investigational Medicinal Product Compliance Injection (Full 
Administration / Interruption) (Randomized Subjects) 
SMED-3 
Investigational Medicinal Product Compliance Tablet (Randomized 
Subjects) 
SUBEX-1 
Subjects Excluded From Analysis Set (Randomized Subjects) 
PDATA-1 
Study Completion Status and Reason for Discontinuation (Randomized 
Subjects) 
PDATA-2 
Inclusion Criteria and Exclusion Criteria Not Met (Randomized Subjects) 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
41 of 43 
Version 1.0 Date: 06/21/2018 
PDATA-3.1 
Medical History and Complications (Randomized Subjects) 
PDATA-3.2 
History of Congestive Heart Failure (Randomized Subjects) 
PDATA-4.1 
Concomitant Medications (Randomized Subjects) 
PDATA-4.2 
Concomitant Therapy Other Than Medication (Randomized Subjects) 
PDATA-5.1.1 Vital Signs (Randomized Subjects) 
PDATA-5.1.2 Vital Signs (from ADaM) (Randomized Subjects) 
PDATA-5.2 
Body Weight and Height (Randomized Subjects) 
PDATA-6.1.1 Electrocardiogram Results Central ECG Analysis Laboratory 
(Randomized Subjects) 
PDATA-6.1.2 Electrocardiogram Results Central ECG Analysis Laboratory (from 
ADaM) (Randomized Subjects) 
PDATA-6.2.1 Electrocardiogram Results Trial Site (Randomized Subjects) 
PDATA-6.2.2 Electrocardiogram Results Trial Site (from ADaM) (Randomized 
Subjects) 
PDATA-7 
Pharmacokinetic Blood Draw Time (Randomized Subjects) 
PDATA-8 
Screen Failures 
PDATA-9 
Physical Examination (Randomized Subjects) 
PDATA-10 
Serum Sodium Concentration, Serum Potassium Concentration 
(Randomized Subjects) 
PDATA-11 
Serum Osmolality, Plasma AVP Concentration, Plasma BNP 
Concentration, Plasma Renin Activity (Randomized Subjects) 
PDATA-12 
Serum NT pro BNP Concentration, Serum Troponin Concentration 
(Randomized Subjects) 
PDATA-13 
Daily Urine Volume, Urine Sodium Concentration, Urine Osmolality and 
Urine Potassium Concentration (Randomized Subjects) 
PDATA-14 
Daily Fluid Intake (Randomized Subjects) 
PDATA-15 
Previous Screened ID and Previous Enrolled Trial (Randomized 
Subjects) 
PDATA-16 
Post-treatment Follow-up (Randomized Subjects) 
PDATA-17 
Pharmacogenomics (Randomized Subjects) 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
42 of 43 
Version 1.0 Date: 06/21/2018 
PDATA-18 
Informed Consent (Randomized Subjects) 
EFF-1 
Body Weight (from ADaM) (Randomized Subjects) 
EFF-2.1 
Congestive Symptoms (Lower Limb Edema, Other Edema, Juglar 
Venous Distension, Hepatomegaly, Pulmonary rales, Third Cardiac 
Sound) (Randomized Subjects) 
EFF-2.2 
Congestive Symptoms (Lower Limb Edema, Juglar Venous Distension, 
Hepatomegaly, Pulmonary rales, Third Cardiac Sound) (from ADaM) 
(Randomized Subjects) 
EFF-3.1 
Chest X-ray (Pulmonary Congestion, Cardiothoracic Ratio) (Randomized 
Subjects) 
EFF-3.2 
Chest X-ray (Pulmonary Congestion, Cardiothoracic Ratio) (Randomized 
Subjects) (from ADaM) 
EFF-4.1 
NYHA Classification (Randomized Subjects) 
EFF-4.2 
NYHA Classification (from ADaM) (Randomized Subjects) 
EFF-5 
Pharmacodynamics Parameter (from ADaM) (Randomized Subjects) 


Protocol 263-102-00001 
 
Statistical Analysis Plan  
43 of 43 
Version 1.0 Date: 06/21/2018 
Appendix 3 
Molecular Weight and Quantitation Limit of Plasma Drug 
Concentration 
Analyte 
Molecular Weighta) 
Lower Limit of Quantitation (ng/mL)b) 
OPC-61815 
572.88 (sodium salt) 
Not Appreciable 
528.92 (free base) 
2.00 
OPC-41061 
448.94 
2.00 
DM-4103 
478.92 
2.00 
DM-4107 
480.94 
2.00 
a): Molecular Weight Information, Issued on 1 Apr 2016 
b): Study Protocol (Study No. P17-21515, Issued on 9 Feb 2018)