A Multicenter, Open-labeled, Dose-defining Trial to Investigate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Tolvaptan in Pediatric Congestive Heart Failure (CHF) Patients With Volume Overload
Phase: PHASE3
Conditions: Pediatric Congestive Heart Failure (CHF) Patients With Volume Overload
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Multicenter, Open-label, Dose-defining Trial to Investigate the Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics of Tolvaptan in Pediatric Heart Failure 
Patients With Volume Overload 
 
 
NCT Number: NCT03255226 
PRT NO.: 156-102-00123 
Version Date: 03 Feb 2021 (Version 4.0) 

 
 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
 
OPC-41061 (Tolvaptan) 
 
CLINICAL PROTOCOL 
Translation 
 
A Multicenter, Open-label, Dose-defining Trial to Investigate the Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics of Tolvaptan in Pediatric Heart Failure 
Patients With Volume Overload 
 
Protocol No. 156-102-00123 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase: 
3 
 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
Immediately Reportable Event  
Office of Pharmacovigilance Operation, 
Department of Pharmacovigilance 
Otsuka Pharmaceutical Co., Ltd 
Email: IRE_156-102-00123@otsuka.jp 
Fax: +81-6-6942-3692 
 
Issue Date: 
03 Feb 2021 
 
Version No.: 
4.0 
 
Date of Translation: 
24 Aug 2021 
 
 
 

 
 
Protocol 156-102-00123 
 
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Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical Co., Ltd 
Name of Investigational Medicinal Product:  
tolvaptan (OPC-41061) 
Protocol No.: 156-102-00123 
 
Protocol Title: 
A Multicenter, Open-label, Dose-defining Trial to Investigate 
the Efficacy, Safety, Pharmacokinetics, and 
Pharmacodynamics of Tolvaptan in Pediatric Heart Failure 
Patients With Volume Overload 
Clinical Phase/ 
Trial Type: 
3 
Dose-defining 
Treatment Indication:  For the treatment of volume overload despite having received 
conventional diuretic therapy in pediatric heart failure patients 
age 6 months to less than 15 years 
Objective(s):  
Primary: To determine the efficacy, safety, and dose and 
regimen of tolvaptan in pediatric heart failure patients with 
volume overload 
Secondary: To determine the pharmacokinetics and 
pharmacodynamics of tolvaptan when administered to 
pediatric heart failure patients with volume overload 
Trial Design: 
Multicenter, open-label, uncontrolled, dose-titration trial 
Subject Population: 
The planned number of subjects for receiving tolvaptan is set 
at 60. 
The subject population includes male or female pediatric heart 
failure patients age 6 months to less than 15 years with volume 
overload despite having received conventional diuretic 
therapy. 
Inclusion/Exclusion 
Criteria:  
[Inclusion Criteria] 
1) Male or female patients age 6 months to less than 15 
years at the time of informed consent by a legal 
representative 
2) Patients with volume overload despite having received 
any of the following diuretic therapies in whom 
sufficient effects cannot be expected even if the dose of 
the diuretics is increased or in whom the investigator or 
subinvestigator judges that increasing the dose of the 
diuretics is difficult due to concerns regarding 
electrolyte abnormalities or other side effects 

 
 
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 Furosemide (oral administration) ≥0.5 mg/kg/day 
 Azosemide 30 mg and torasemide 4 mg will be 
calculated as equivalent to furosemide 20 mg. 
 Hydrochlorothiazide ≥2 mg/kg/day 
 Trichlormethiazide ≥0.05 mg/kg/day 
 Spironolactone ≥1 mg/kg/day 
3) Patients capable of complaining of thirst. Patients 
unable to complain of thirst due to their young age can 
also be enrolled in the trial if strict management of 
fluid intake and excretion is conducted (frequent 
monitoring during the 8 hours after start of tolvaptan 
administration and at the time of dose-increase, and at 
least as frequent as every 8 hours at other times). 
However, even if such fluid management is possible, 
patients in whom the investigator or subinvestigator 
judges that tolvaptan cannot be safely administered are 
to be excluded. 
4) Patients who can be hospitalized from at least 3 days 
before start of tolvaptan administration until 2 days 
after final administration 
 
[Main Exclusion Criteria] 
1) Patients whose volume overload status shows 
improvement during the screening period or 
pretreatment observation period 
2) Patients who are unable to drink fluid (including 
patients who are unable to sense thirst) 
3) Patients whose circulatory blood flow is suspected to 
be decreased 
4) Patients with an assisted circulation apparatus 
5) Patients with hypernatremia (serum or blood sodium 
concentration exceeding 145 mEq/L) 
6) Patients with serum or blood potassium exceeding the 
upper limit of the reference range for their age and 
gender. 
7) Patients with a history or concurrent condition of liver 
impairment, including those with aspartate 
aminotransferase (AST) or alanine aminotransferase 
(ALT) ≥3 times the upper limit of the reference range 
for their age and gender at the time of the screening 
examination or during the pretreatment observation 

 
 
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period 
8) Patients with serum creatinine corresponding to Stage 3 
or higher in the CKD Stage Assessment Using Serum 
Creatinine Level (mg/dL) Chart in the renal function 
assessment at the time of diagnosis of pediatric chronic 
kidney disease (pediatric CKD) 
9) Patients with anuria 
10) Patients with urinary excretion disorders due to urinary 
stenosis, urinary calculus, tumor, etc 
Trial Site(s):  
Approximately 30 trial sites in Japan 
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration: 
Subjects will take tolvaptan 1% granules or tolvaptan 15 mg 
tablet with water once daily after breakfast. 
The initial dose of tolvaptan will be 0.05 mg/kg/day. From the 
second day of the treatment period and onward, if necessary 
the dose may be increased to 0.15, 0.3, or 0.5 mg/kg/day 
according to the rules specified in Section 3.2.2, and then the 
dose decided for each individual subject will be administered 
for 3 days. The dose of tolvaptan 1% granules to be 
administered will be determined depending on the subject’s 
body weight on the day before start of tolvaptan 
administration; however, the maximum dose is 15 mg/day 
even if the calculated dose exceeds 15 mg/day. For 
administration at the maximum dose of 15 mg, tolvaptan 
15-mg tablet may be administered in place of tolvaptan 1% 
granules. Regarding dose reduction or extension of treatment 
with tolvaptan, refer to Section 3.2.3 and Section 3.2.4. 
Trial Assessments: 
Efficacy: Body weight, daily urine volume, edematous 
symptoms (edema [lower limbs, eyelids, etc], dyspnea, jugular 
venous distension, respiration rate at rest, and pulse rate), chest 
x-ray (pulmonary congestion, cardiothoracic ratio, and pleural 
effusion), central venous pressure (only subjects with central 
venous catheterization), and retention of pericardial effusion 
(only subjects requiring echocardiography) 
Pharmacodynamics: Daily fluid intake, serum osmolality, 
serum or blood sodium concentration, serum or blood 
potassium concentration, urine osmolality, urine 
concentrations of sodium and potassium, and plasma arginine 
vasopressin (AVP) concentration (only subjects from whom 
samples are available) 
Pharmacokinetics: Blood sampling for measurement of plasma 
drug concentration 

 
 
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Safety: Adverse event (AE) reporting, clinical laboratory tests, 
vital signs, 12-lead electrocardiogram, and pregnancy test 
(only for female subjects who have begun menstruation) 
Criteria for 
Evaluation: 
Primary Endpoint: 
The percentage of subjects who satisfy the following 
condition: 
 Body weight on the day after the third day of treatment 
with tolvaptan at the evaluation dose (see Section 7.4) 
is decreased by 1.7% or more from the weight 
measured before breakfast on the first day of the 
treatment period 
However, mean daily urine volume for the 3 days of treatment 
with tolvaptan at the evaluation dose must be higher than the 
daily urine volume for the pretreatment observation period. 
For subjects who discontinued treatment with tolvaptan, mean 
daily urine volume up until the time of discontinuation must be 
higher than the daily urine volume for the pretreatment 
observation period. 
 
Secondary Endpoint(s): 
 Body weight 
 Edematous symptoms (edema [lower limbs, eyelids, 
etc], dyspnea, jugular venous distension, pulmonary 
congestion, cardiothoracic ratio, respiration rate at rest, 
pulse rate, and pleural effusion), central venous 
pressure (only subjects with central venous 
catheterization), and retention of pericardial effusion 
(only subjects requiring echocardiography to confirm 
retention of pericardial effusion prior to tolvaptan 
administration) 
 Daily urine volume 
Statistical Methods: 
[Statistical Methods for Primary Endpoint] 
The number and percentage of subjects whose body weight on 
the day after the third day of treatment with tolvaptan at the 
evaluation dose is decreased by 1.7% or more from the weight 
measured before breakfast on the first day of the treatment 
period will be calculated together with exact 95% confidence 
intervals (CI) based on binomial distribution. The same 
calculations will be performed regarding body weight on the 
day after final tolvaptan administration. The number and 
percentage of subjects will also be calculated for each time 

 
 
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point after the start of treatment at the tolvaptan evaluation 
dose using body weight on the first day of administration at the 
evaluation dose as the baseline.  
[Rationale for the Sample Size] 
For the primary endpoint, the required sample size was set by 
first setting the threshold value for assessment of efficacy, and 
then using binomial distribution to determine the number of 
subjects required to maintain a 90% or higher probability that 
the lower limit of the 95% CI for the percentage of subjects 
achieving the primary endpoint will be above the threshold 
value. 
As reference information for the threshold value and binomial 
distribution parameter required to set the sample size for the 
trial, a threshold of 0.3 and a binomial distribution parameter 
of 0.5 to 0.6 were used based on interviews with clinicians, 
since no clinical trial results for administration of tolvaptan in 
pediatric patients have been obtained either in Japan or other 
countries. 
Based on the above, the required number of subjects was 
calculated to be a minimum of 68 for a parameter of 0.5 and a 
minimum of 30 for a parameter of 0.6. 
A sample size of 30 to 68 subjects was therefore considered to 
be appropriate, and in view of feasibility the number of 
subjects for the trial was set at 60. 
Trial Duration: 
Duration of the trial: May 2017 to Nov 2021 
Expected duration of trial participation for individual subjects: 
Maximum 27 days 
(0 to 4 days for screening period, 3 days for pretreatment 
observation period, 5 to 15 days for treatment period, and 3 to 
5 days for follow-up) 
 
 

 
 
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Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ........................................................................................... 7 
List of In-text Tables ................................................................................... 14 
List of In-text Figures .................................................................................. 15 
List of Appendices........................................................................................ 16 
List of Abbreviations and Definitions of Terms ....................................... 17 
1 
Introduction ........................................................................................ 18 
1.1 
Nonclinical Data ................................................................................................18 
1.2 
Clinical Data ......................................................................................................18 
1.2.1 
A Dose-ranging Trial in Adult Heart Failure Patients With Volume 
Overload in Japan (Trial 156-03-001) ............................................................18 
1.2.2 
A Phase 3, Double-blind, Placebo-controlled Trial in Adult Heart 
Failure Patients With Volume Overload in Japan (Trial 156-06-002) ...........19 
1.3 
Known and Potential Risks and Benefits ..........................................................20 
2 
Trial Rationale and Objectives.......................................................... 21 
2.1 
Trial Rationale ...................................................................................................21 
2.2 
Dosing Rationale ...............................................................................................21 
2.3 
Trial Objectives .................................................................................................23 
3 
Trial Design ......................................................................................... 23 
3.1 
Type/Design of Trial .........................................................................................23 
3.2 
Trial Treatments ................................................................................................25 
3.2.1 
Dose and Regimen ..........................................................................................25 
3.2.2 
Increasing the Dose of Tolvaptan ...................................................................25 
3.2.3 
Reducing the Dose of Tolvaptan ....................................................................26 
3.2.4 
Extended Treatment With Tolvaptan ..............................................................26 
3.2.5 
Treatment Period ............................................................................................27 
3.2.6 
Hospitalization ................................................................................................28 
3.3 
Trial Population .................................................................................................28 
3.3.1 
Number of Subjects and Description of Population .......................................29 
3.3.2 
Subject Selection and Numbering ..................................................................29 

 
 
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3.4 
Eligibility Criteria..............................................................................................30 
3.4.1 
Informed Consent ...........................................................................................30 
3.4.2 
Inclusion Criteria ............................................................................................31 
3.4.3 
Exclusion Criteria ...........................................................................................32 
3.5 
Endpoints ...........................................................................................................33 
3.5.1 
Primary Endpoint ............................................................................................33 
3.5.2 
Secondary Endpoints ......................................................................................33 
3.6 
Measures to Minimize/Avoid Bias ....................................................................34 
3.7 
Trial Procedures ................................................................................................34 
3.7.1 
Schedule of Assessments ................................................................................37 
3.7.1.1 
Screening Period (7 to 3 Days Before Start of Tolvaptan 
Administration) ...........................................................................................37 
3.7.1.2 
Pretreatment Observation Period ................................................................37 
3.7.1.2.1 
Pretreatment Observation Period (3 Days Before Start of Tolvaptan 
Administration) ........................................................................................37 
3.7.1.2.2 
Pretreatment Observation Period (2 Days Before Start of Tolvaptan 
Administration) ........................................................................................38 
3.7.1.2.3 
Pretreatment Observation Period (1 Day Before Start of Tolvaptan 
Administration) ........................................................................................38 
3.7.1.3 
Treatment Period .........................................................................................39 
3.7.1.3.1 
Day 1 of Treatment Period ......................................................................39 
3.7.1.3.2 
Day 2 of Treatment Period ......................................................................40 
3.7.1.3.3 
Day 3 of Treatment Period ......................................................................41 
3.7.1.3.4 
Day 4 of Treatment Period ......................................................................42 
3.7.1.3.5 
Day 5 of Treatment Period ......................................................................43 
3.7.1.3.6 
Day 6 of Treatment Period ......................................................................44 
3.7.1.3.7 
Day 7 of Treatment Period ......................................................................45 
3.7.1.3.8 
Day 8 of Treatment Period ......................................................................46 
3.7.1.3.9 
Day 9 of Treatment Period ......................................................................47 
3.7.1.3.10 
Day After Final Administration ...............................................................48 
3.7.1.3.11 
Two Days After Final Administration .....................................................49 
3.7.1.4 
Extended Treatment With Tolvaptan at Dose Decided for Each 
Individual Subject From Fourth Day ..........................................................49 

 
 
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3.7.1.4.1 
Fourth Day of Administration at Dose Decided for Each Individual 
Subject .....................................................................................................49 
3.7.1.4.2 
Fifth Day of Administration at Dose Decided for Each Individual 
Subject .....................................................................................................50 
3.7.1.4.3 
Sixth Day of Administration at Dose Decided for Each Individual 
Subject .....................................................................................................51 
3.7.1.4.4 
Seventh Day of Administration at Dose Decided for Each 
Individual Subject ....................................................................................52 
3.7.1.4.5 
Day After Final Administration in Extended Treatment .........................53 
3.7.1.4.6 
Two Days After Final Administration in Extended Treatment ...............53 
3.7.1.5 
Extended Treatment With Tolvaptan at Reduced Dose ..............................53 
3.7.1.5.1 
First Day of Administration at Reduced Dose ........................................54 
3.7.1.5.2 
Second Day of Administration at Reduced Dose ....................................55 
3.7.1.5.3 
Third Day of Administration at Reduced Dose .......................................55 
3.7.1.5.4 
Fourth Day of Administration at Reduced Dose .....................................56 
3.7.1.5.5 
Day After Final Administration in Extended Treatment at Reduced 
Dose .........................................................................................................57 
3.7.1.5.6 
Two Days After Final Administration in Extended Treatment at 
Reduced Dose ..........................................................................................58 
3.7.1.6 
Treatment Discontinuation ..........................................................................58 
3.7.1.7 
Follow-up Period (5 to 7 Days After Final Tolvaptan Administration)......59 
3.7.2 
Efficacy Assessments .....................................................................................59 
3.7.2.1 
Body Weight ...............................................................................................59 
3.7.2.2 
Daily Urine Volume ....................................................................................60 
3.7.2.3 
Edematous Symptoms (Edema [Lower Limbs, Eyelids, etc], Dyspnea, 
Jugular Venous Distension, Respiration Rate at Rest, and Pulse Rate) ......60 
3.7.2.3.1 
Edema (Lower Limbs, Eyelids, etc) ........................................................60 
3.7.2.3.1.1 
Edema (Lower Limbs) .........................................................................60 
3.7.2.3.1.2 
Edema (Eyelids) ...................................................................................60 
3.7.2.3.1.3 
Edema (Others) ....................................................................................61 
3.7.2.3.2 
Dyspnea ...................................................................................................61 
3.7.2.3.3 
Jugular Venous Distension ......................................................................61 
3.7.2.3.4 
Respiration Rate at Rest ..........................................................................61 
3.7.2.3.5 
Pulse Rate ................................................................................................61 

 
 
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3.7.2.4 
Chest X-ray (Pulmonary Congestion, Cardiothoracic Ratio, and 
Pleural Effusion) .........................................................................................61 
3.7.2.4.1 
Pulmonary Congestion ............................................................................61 
3.7.2.4.2 
Cardiothoracic Ratio ................................................................................62 
3.7.2.4.3 
Pleural Effusion .......................................................................................62 
3.7.2.5 
Central Venous Pressure (Only Subjects With Central Venous 
Catheterization) ...........................................................................................62 
3.7.2.6 
Retention of Pericardial Effusion (Only Subjects Requiring 
Echocardiography) ......................................................................................62 
3.7.3 
Safety Assessments .........................................................................................62 
3.7.3.1 
Adverse Events............................................................................................62 
3.7.3.2 
Laboratory tests ...........................................................................................63 
3.7.3.3 
Vital signs ...................................................................................................64 
3.7.3.3.1 
Body Temperature ...................................................................................64 
3.7.3.3.2 
Blood Pressure and Pulse Rate ................................................................64 
3.7.3.4 
12-lead Electrocardiogram ..........................................................................64 
3.7.3.5 
Pregnancy Test ............................................................................................64 
3.7.4 
Pharmacokinetic/Pharmacodynamic Assessments .........................................65 
3.7.4.1 
Pharmacokinetic Assessments ....................................................................65 
3.7.4.1.1 
Pharmacokinetic Blood Samples .............................................................65 
3.7.4.2 
Pharmacodynamic Assessments .................................................................66 
3.7.4.2.1 
Daily fluid intake .....................................................................................66 
3.7.4.2.2 
Daily Fluid Balance .................................................................................66 
3.7.4.2.3 
Serum Osmolality ....................................................................................66 
3.7.4.2.4 
Serum or Blood Sodium Concentration ..................................................67 
3.7.4.2.5 
Serum or Blood Potassium Concentration ..............................................67 
3.7.4.2.6 
Urine Osmolality .....................................................................................67 
3.7.4.2.7 
Daily Urine Sodium Excretion ................................................................68 
3.7.4.2.8 
Daily Urine Potassium Excretion ............................................................69 
3.7.4.2.9 
Plasma AVP Concentration .....................................................................69 
3.7.5 
End of Trial .....................................................................................................70 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures ......................................70 

 
 
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3.8.1 
Entire Trial ......................................................................................................70 
3.8.2 
Individual Site Discontinuation ......................................................................70 
3.8.3 
Individual Subject Discontinuation ................................................................70 
3.8.3.1 
Treatment Discontinuation ..........................................................................70 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation ...............................71 
3.8.3.3 
Withdrawal of Consent ...............................................................................72 
3.8.3.4 
Procedures to Encourage Continued Trial Participation .............................73 
3.9 
Screen Failures ..................................................................................................73 
3.10 
Definition of Completed Subjects .....................................................................74 
3.11 
Definition of Subjects Lost to Follow-up ..........................................................74 
3.12 
Legal Representative or Subject Compliance ...................................................75 
3.13 
Protocol Deviations ...........................................................................................75 
4 
Restrictions .......................................................................................... 76 
4.1 
Prohibited Concomitant Medications ................................................................76 
4.2 
Restricted Concomitant Medications ................................................................77 
5 
Reporting of Adverse Events ............................................................. 78 
5.1 
Definitions .........................................................................................................78 
5.2 
Eliciting and Reporting Adverse Events ...........................................................80 
5.3 
Immediately Reportable Events ........................................................................80 
5.4 
Potential Drug Induced Liver Injury .................................................................81 
5.5 
Pregnancy ..........................................................................................................81 
5.6 
Procedure for Breaking the Blind ......................................................................82 
5.7 
Follow-up of Adverse Events ............................................................................82 
5.7.1 
Follow-up of Nonserious Adverse Events ......................................................83 
5.7.2 
Follow-up of Serious Adverse Events ............................................................83 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring After 
End of Trial Date (Last Scheduled Contact) ...................................................83 
6 
Pharmacokinetic/Pharmacodynamic Analysis ................................ 84 
6.1 
Pharmacokinetic Analysis .................................................................................84 
6.2 
Pharmacodynamic Analysis ..............................................................................84 
7 
Statistical Analysis .............................................................................. 85 

 
 
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7.1 
Sample Size .......................................................................................................85 
7.2 
Datasets for Analysis .........................................................................................86 
7.3 
Handling of Missing Data .................................................................................86 
7.4 
Definition of Evaluation Dose ...........................................................................86 
7.5 
Primary and Secondary Endpoint Analyses ......................................................87 
7.5.1 
Primary Endpoint Analysis .............................................................................87 
7.5.2 
Secondary Endpoint Analysis .........................................................................87 
7.5.2.1 
Percent Change in Body Weight .................................................................87 
7.5.2.2 
Edematous Symptoms (Edema [Lower Limbs, Eyelids, etc], Dyspnea, 
Jugular Venous Distension, Pulmonary Congestion, Cardiothoracic 
Ratio, Respiration Rate at Rest, Pulse Rate, and Pleural Effusion), 
Central Venous Pressure (Only Subjects With Central Venous 
Catheterization), and Retention of Pericardial Effusion (Only 
Subjects Requiring Echocardiography).......................................................88 
7.5.2.2.1 
Edema (Lower Limbs, etc) and Pulmonary Congestion .........................88 
7.5.2.2.2 
Edema (Eyelids), Jugular Venous Distension, Dyspnea, and Pleural 
Effusion ...................................................................................................89 
7.5.2.2.3 
Cardiothoracic Ratio, Respiration Rate at Rest, and Pulse Rate .............89 
7.5.2.2.4 
Central Venous Pressure ..........................................................................89 
7.5.2.2.5 
Retention of Pericardial Effusion ............................................................89 
7.5.2.3 
Daily Urine Volume ....................................................................................89 
7.6 
Analysis of Demographic and Baseline Characteristics....................................90 
7.7 
Safety Analysis ..................................................................................................90 
7.7.1 
Adverse Events ...............................................................................................90 
7.7.2 
Clinical Laboratory Data ................................................................................90 
7.7.3 
Vital Signs Data ..............................................................................................91 
7.7.4 
12-lead Electrocardiogram Data .....................................................................91 
8 
Management of Investigational Medicinal Product ........................ 92 
8.1 
Packaging and Labeling ....................................................................................92 
8.2 
Storage ...............................................................................................................92 
8.3 
Accountability ...................................................................................................92 
8.4 
Returns and Destruction ....................................................................................92 
8.5 
Reporting of Product Quality Complaints .........................................................92 

 
 
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8.5.1 
Eliciting and Reporting Product Quality Complaints .....................................93 
8.5.2 
Information Required for Reporting Product Quality Complaints .................93 
8.5.3 
Return Process for Product Quality Complaints .............................................94 
8.5.4 
Assessment/Evaluation ...................................................................................94 
9 
Records Management ......................................................................... 94 
9.1 
Source Documents .............................................................................................94 
9.2 
Data Collection ..................................................................................................94 
9.3 
File Management at the Trial Site .....................................................................95 
9.4 
Records Retention at the Trial Site....................................................................96 
10 
Quality Control and Quality Assurance ........................................... 96 
10.1 
Monitoring .........................................................................................................96 
10.2 
Auditing .............................................................................................................96 
11 
Ethics and Responsibility ................................................................... 97 
12 
Confidentiality .................................................................................... 97 
13 
Amendment Policy .............................................................................. 98 
14 
Publication Authorship Requirements ............................................. 98 
15 
References ............................................................................................ 99 
 

 
 
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List of In-text Tables 
Table 3.4.2-1 
Inclusion Criteria ...........................................................................31 
Table 3.4.3-1 
Exclusion Criteria ..........................................................................32 
Table 3.7-1 
Basic Assessment Schedule Without Reduction of Dose or 
Extension of Treatment ..................................................................35 
Table 3.7.2.3.1.1-1 
Criteria for Grading Lower Limb Edema ......................................60 
Table 3.7.2.4.1-1 
Criteria for Grading Pulmonary Congestion ..................................62 
Table 3.7.3.2-1 
Clinical Laboratory Assessments ...................................................63 
Table 4.1-1 
List of Medications Prohibited Before the Trial ............................76 
Table 4.1-2 
Drugs and Foods That May Be a Strong Inhibitors or 
Inducers of CYP3A4 ......................................................................76 
Table 7.5.2.2.1-1 
Degree of Improvement for Edema and Pulmonary 
Congestion 
................................................................................88 
 
 

 
 
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List of In-text Figures 
Figure 3.1-1 
Basic Trial Design Schematic ........................................................24 
Figure 3.2.4-1 
Patterns of Treatment With Tolvaptan Including Extended 
Treatment  
................................................................................27 
 
 

 
 
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List of Appendices 
Appendix 1 
Handling and Shipment of Bioanalytical Samples ......................100 
Appendix 2 
Protocol Amendment(s)/Administrative Change(s) ....................101 
 
 

 
 
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List of Abbreviations and Definitions of Terms 
Abbreviation Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AVP 
Arginine vasopressin 
CKD 
Chronic Kidney Disease 
CHF 
Congestive heart failure 
CRF 
Case report form 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
GCP 
Good Clinical Practice  
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
IAF 
Informed assent form 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors  
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
PQC 
Product quality complaint 
SAE 
Serious adverse event 
TEAE 
Treatment-emergent adverse event 
 
 
 

 
 
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1 
Introduction 
1.1 
Nonclinical Data 
Tolvaptan is a vasopressin V2-receptor antagonist that specifically blocks the binding of 
arginine vasopressin (AVP) at the V2 receptors of the distal portions of the nephron, 
thereby inducing water diuresis (aquaresis) without depletion of electrolytes. 
In a beagle dog model of congestive heart failure (CHF), tolvaptan produced a significant 
decrease in cardiac preload without affecting cardiac afterload or renal functions. 
Consequently, tolvaptan can be expected to be useful for the treatment of the volume 
overload state of heart failure without having any undesirable effects on renal function, 
systemic hemodynamics, or circulating neurohormones. For detailed data, see the 
Investigator’s Brochure (IB). 
 
1.2 
Clinical Data 
1.2.1 
A Dose-ranging Trial in Adult Heart Failure Patients With Volume 
Overload in Japan (Trial 156-03-001) 
A total of 122 adult heart failure patients with volume overload whose condition had not 
been resolved by the use of furosemide (at 40 mg/day or more) received 7-day repeated 
oral administration of tolvaptan at 15 mg/day, 30 mg/day, and 45 mg/day or placebo. 
As a result, a change in body weight from baseline (mean) was observed from the day 
after the first administration in all tolvaptan groups. Decreases in body weight following 
7-day repeated administration of tolvaptan at 15 mg/day, 30 mg/day, and 45 mg/day were 
significantly greater than those seen in the placebo group; however, the degree of change 
was similar across all tolvaptan doses. 
Incidence of adverse events (AEs) was 62.1% (18/29 subjects, 55 events) in the placebo 
group while it was 85.7% (24/28 subjects, 72 events), 97.0% (32/33 subjects, 92 events), 
and 82.1% (23/28 subjects, 63 events) in the tolvaptan 15 mg, 30 mg, and 45 mg groups, 
respectively. The most frequently reported AEs were thirst and dehydration, considered 
to be due to the pharmacological effects of tolvaptan, and the number of subjects who 
experienced these events increased dose-dependently in the tolvaptan groups. Incidence 
of adverse reactions was 37.9% (11/29 subjects, 22 events) in the placebo group while 
60.7% (17/28 subjects, 42 events), 63.6% (21/33 subjects, 51 events), and 75.0% (21/28 
subjects, 45 events) in the tolvaptan 15 mg, 30 mg, and 45 mg groups, respectively. Most 

 
 
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of observed adverse reactions were transient and resolved or improved through 
appropriate treatment. 
Two subjects died (sudden death and cardio-respiratory arrest), both of whom were in the 
placebo group. Serious adverse events (SAEs) other than death were observed in 5 
subjects: 2 (heart failure congestive andumbilical hernia) in the placebo group, 1 
(epistaxis) in the 30 mg group, and 2(dyspnoea exertional and transient ischaemic attack) 
in the 45 mg group. For all of these events excluding those observed in 1 subject in the 
placebo group (cardio-respiratory arrest) and 1 subject in the tolvaptan 45 mg group 
(dyspnoea exertional), a causal relationship with the investigational medicinal product 
(IMP) was ruled out. Treatment discontinuation due to AEs occurred in 3 subjects in the 
placebo group (dehydration, renal impairment, and hyperkalaemia; pleural effusion and 
dyspnoea exertional; cardiac failure), no subjects in the tolvaptan 15 mg group, 2 subjects 
in the tolvaptan 30 mg group (dehydration, malaise), 5 subjects in the tolvaptan 45 mg 
group (dehydration and renal impairment; dyspnoea exertional; blood urea increased; 
blood potassium increased; blood pressure decreased). For all of these events, a causal 
relationship with the IMP was not ruled out. All SAEs, and AEs leading to 
discontinuation were resolved by treatment discontinuation or other appropriate measures. 
For detailed data, see the IB. 
1.2.2 
A Phase 3, Double-blind, Placebo-controlled Trial in Adult Heart 
Failure Patients With Volume Overload in Japan (Trial 156-06-002) 
A total of 110 adult heart failure patients with volume overload whose condition had not 
been resolved by conventional diuretic therapy received 7-day administration of tolvaptan 
at 15 mg/day or placebo. 
As a result, a change in body weight at final administration (mean ± standard deviation) 
was −1.54 ± 1.61 kg in the tolvaptan 15 mg group, and −0.45 ± 0.93 kg in the placebo 
group. Body weight in the tolvaptan 15 mg group decreased significantly in comparison 
with the placebo group (p < 0.0001 by t-test), and a difference in the mean change 
between the tolvaptan 15 mg group and the placebo group was −1.09 kg (95% CI: −1.58 
to −0.60 kg). 
Adverse events occurring in the tolvaptan 15 mg group at an incidence of 3% or higher 
and also at an incidence of at least 3% higher than in the placebo group were thirst 
(17.0% [9/53 subjects] in the tolvaptan 15 mg group, 1.8% [1/57 subjects] in the placebo 
group), constipation (17.0% [9/53 subjects], 5.3% [3/57 subjects]), pollakiuria (9.4% 
[5/53 subjects], 0.0%), nausea and malaise (5.7% [3/53 subjects], 0.0%), and dizziness 

 
 
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and headache (3.8% [2/53 subjects], 0.0%). All of these AEs were mild or moderate in 
severity. The events of thirst, constipation, and pollakiuria were probably due to the 
diuretic action of tolvaptan. 
Serious AEs occurred in 2 subjects in the tolvaptan 15 mg group and 7 subjects in the 
placebo group. 
Of the 2 subjects in the tolvaptan 15 mg group, one subject died, and in that subject renal 
failure chronic (SAE) and cardiac failure (AE resulting in death) were reported. In the 
other subject, atrial fibrillation was reported as a SAE. For detailed data, see the IB. 
 
1.3 
Known and Potential Risks and Benefits 
In trials in adult heart failure patients with volume overload (Trials 156-03-001, 
156-06-002, 156-06-004, 156-06-006, 156-10-005, 156-TWA-1101i, and 156-12-809-01), 
The most frequently reported AEs in 437 subjects treated with tolvaptan (with an 
incidence of >3% of all tolvaptan treated subjects) were as follows: Thirst, blood urea 
increased, blood uric acid increased, constipation, cardiac failure, blood creatinine 
increased, blood potassium increased, pollakiuria, dry mouth, dehydration, dizziness, 
nasopharyngitis, hyperuricaemia, diarrhoea, and hypokalaemia. The most frequently 
reported AEs with an incidence of >5% in placebo group were cardiac failure and 
hypokalaemia. The AEs with a higher incidence in subjects treated with oral tolvaptan at 
all doses than in subjects receiving placebo (with an incidence of >5% of all tolvaptan 
treated subjects and a higher incidence than that of subjects receiving placebo) were 
blood uric acid increased, constipation, blood creatinine increased, and blood potassium 
increased. In patients with volume overload that had not been resolved despite having 
received furosemide, administration of tolvaptan (15 mg, 30 mg, and 45 mg) decreased 
body weight significantly and increased urine volume dose-dependently. In the tolvaptan 
groups, edematous symptoms, such as lower limb edema and jugular venous distension, 
showed an improvement compared with the placebo group. For the details of AEs 
attributable to tolvaptan therapy in clinical trials, see the IB. 
 

 
 
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2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
Tolvaptan is a vasopressin V2-receptor antagonist synthesized by Otsuka Pharmaceutical 
Co., Ltd., which specifically blocks the binding of AVP at the V2 receptors of the distal 
portions of the nephron to induce water diuresis (aquaresis) without depletion of 
electrolytes. Tolvaptan was approved in Japan in Oct 2010 for the indication of the 
treatment for adult patients with “volume overload in heart failure when adequate 
response is not obtained with other diuretics (eg, loop diuretics)”. However, no clinical 
trial has been conducted to evaluate its efficacy and safety in pediatric heart failure 
patients with volume overload. 
Volume overload in pediatric heart failure patients is caused by diverse etiologies, and 
diuretics are widely used to treat it. The diuretics used for pediatric patients, as in adult 
patients, are conventional diuretics, eg, mainly loop diuretics. Tolvaptan, which has a 
mechanism of action different from that of conventional diuretics, is expected to become 
a useful therapeutic approach to improve volume overload in pediatric heart failure 
patients when adequate response is not obtained with conventional diuretics. 
This trial was planned in order to determine the efficacy, safety, pharmacokinetics, and 
pharmacokinetics of tolvaptan in pediatric heart failure patients with volume overload 
despite having received conventional diuretic therapy. 
This protocol was prepared in accordance with the agreement reached with the 
Pharmaceuticals and Medical Devices Agency about the appropriateness of the trial plan 
at the consultation after completion of a phase 2 trial (04 Oct 2016, Application Number 
P4175). 
In view of the above, the conduct of this trial is scientifically and ethically appropriate. 
 
2.2 
Dosing Rationale 
According to the Clinical Guideline for Medical Treatment of Pediatric Heart Failure 
(JSPCCS 2015)1 prepared by the Japanese Society of Pediatric Cardiology and Cardiac 
Surgery, tolvaptan “should be administered at 0.3 to 0.5 mg/kg/day once daily, starting at 
around half of this dose” for pediatric heart failure patients. On the other hand, a lower 
starting dose than that recommended in the guideline is often noted in literatures or case 
reports addressing tolvaptan therapy in pediatric heart failure patients.2 In a retrospective 

 
 
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study collecting the outcomes of pediatric heart failure patients who received tolvaptan 
therapy in Japan,2 a wide range of starting doses was seen (0.02-0.76 mg/kg/day). A 
usual dose of tolvaptan for adult heart failure patients with volume overload is 15 mg/day 
(0.25 mg/kg/day for adults with a body weight of 60 kg). However, the postmarketing 
survey results with 3000 patients showed that the proportion of patients receiving 
tolvaptan at 7.5 mg/day (0.125 mg/kg/day for adults with a body weight of 60 kg) was the 
highest at 52%, and that even the proportion of those at 3.75 mg/day (0.0625 mg/kg/day 
for adults with a body weight of 60 kg) was as high as 9%. Based on these findings, 
tolvaptan can be expected to show a certain efficacy at a starting dose of 0.05 mg/kg/day 
in this trial. On the other hand, the risk for excessive aquaresis should be avoided as some 
patients are highly responsive to tolvaptan. A dose of 0.05 mg/kg/day, which is 
equivalent to 3 mg/day for adults with a body weight of 60 kg, can reduce risks in such 
patients. Consequently, a starting dose was set at 0.05 mg/kg/day in consideration of a 
balance between efficacy and safety. A subsequent dose should be set for each individual 
subject by increasing the dose to 0.15, 0.3, or 0.5 mg/kg/day as per the guideline while 
monitoring each subject’s response because responsiveness to tolvaptan may vary from 
subject to subject. 
In the dose-ranging trial of tolvaptan in adult heart failure patients with volume overload 
(Trial 156-03-001), tolvaptan was administered at 15 mg/day, 30 mg/day, or 45 mg/day, 
and urine volume was increased with an increase in dose. For a decrease in body weight, 
on the other hand, no difference was noted between the 3 doses. This finding 
demonstrated that a dose of 15 mg/day was sufficient to obtain clinical effects. As a result, 
the approved dose of tolvaptan for adult heart failure patients with volume overload was 
determined to be 15 mg/day. The maximum dose in pediatric heart failure patients 
(0.5 mg/kg/day) is equivalent to 30 mg/day (adults with a body weight of 60 kg) in adult 
heart failure patients. This dose is sufficient to obtain an aquaretic effect even the effect 
in pediatric heart failure patients is as weak as around half of that in adults. In the dose-
ranging trial (Trial 156-03-001), 7-day repeated administration of placebo or tolvaptan at 
15 mg/day (0.25 mg/kg/day for adults with a body weight of 60 kg), 30 mg/day 
(0.5 mg/kg/day for adults with a body weight of 60 kg), or 45 mg/day (0.75 mg/kg/day 
for adults with a body weight of 60 kg) resulted in thirst with an incidence of 10.3% in 
the placebo group, 21.4% in the tolvaptan 15 mg/day group, 27.3% in the tolvaptan 
30 mg/day group, and 53.6% in the tolvaptan 45 mg/day group, showing the higher 
incidence of AEs associated with the pharmacological action of tolvaptan in the 
45 mg/day group. It is unlikely that tolvaptan therapy will pose safety issues when its 
maximum dose is set at 30 mg/day (equivalent to 0.5 mg/kg/day in children). The dose of 

 
 
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0.5 mg/kg/day is equivalent to the upper limit on the dose of tolvaptan specified in the 
Clinical Guideline for Medical Treatment of Pediatric Heart Failure. 
Therefore, a trial of tolvaptan using an ascending dose regimen within the range of 0.05 
to 0.5 mg/kg/day can provide information about its appropriate dose and regimen in 
pediatric heart failure patients. 
 
2.3 
Trial Objectives 
Primary: To determine the efficacy, safety, and dose and regimen of tolvaptan in 
pediatric heart failure patients with volume overload 
Secondary: To determine the pharmacokinetics and pharmacodynamics of tolvaptan 
when administered to pediatric heart failure patients with volume overload 
 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multicenter, open-label, uncontrolled, dose-titration trial. In this trial, an 
ascending dose regimen where administration is started at a low dose is employed to 
ensure the safety of subjects. A basic trial design schematic is shown in Figure 3.1-1. 
After completion of a screening examination, subjects will be hospitalized prior to the 
evening meal on 3 days before start of tolvaptan administration. Tolvaptan administration 
will be started at 0.05 mg/kg/day, and subjects with sufficient increase in urine volume 
will continue administration at 0.05 mg/kg/day for 3 days. For subjects whose urine 
volume does not sufficiently increase, the dose may be increased to 0.15, 0.3, or 0.5 
mg/kg/day according to the specification. In that case, the dose should be decided for 
each individual subject to obtain sufficient increase in urine volume, and administration 
at the decided dose will be continued for 3 days. When the dose is increased to 
0.5 mg/kg/day, administration at 0.5 mg/kg/day should be continued for 3 days. After 
final tolvaptan administration, subjects will continue to be hospitalized for 2 days to 
undergo monitoring of condition. Subjects will also undergo the follow up 5 to 7 days 
after final tolvaptan administration. 
 

 
 
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Figure 3.1-1 
Basic Trial Design Schematic 
 
Day −7 to −3 Before
Start of Treatment
Day −3
Before
Start of
Treatment
Day −2
Before
Start of
Treatment
Day −1
Before
Start of
Treatment
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11 5 to 7 Days After Final
Administration
: Increasing dose
+                          : Treatment period
●: Tolvaptan
      administration
: Administration
  period
: Inpatient observation
  period
Treatment Period
Pretreatment 
Observation Period
Screening Period
0.05 mg/kg
0.15 mg/kg
0.3 mg/kg
Follow-up Period
0.5 mg/kg
Mandatory Hospitalization Period
Mandatory Hospitalization Period
Mandatory Hospitalization Period
Mandatory Hospitalization Period

 
 
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3.2 
Trial Treatments 
3.2.1 
Dose and Regimen 
Subjects will take tolvaptan 1% granules or tolvaptan 15 mg tablet with water once daily 
after breakfast. 
The initial dose of tolvaptan will be 0.05 mg/kg/day. From the second day of the 
treatment period and onward, if necessary the dose may be increased to 0.15, 0.3, or 
0.5 mg/kg/day according to the rules specified in Section 3.2.2, and then the dose decided 
for each individual subject will be administered for 3 days. The dose of tolvaptan 1% 
granules to be administered will be determined depending on the subject’s body weight 
on the day before start of tolvaptan administration; however, the maximum dose is 
15 mg/day even if the calculated dose exceeds 15 mg/day. For administration at the 
maximum dose of 15 mg, tolvaptan 15-mg tablet may be administered in place of 
tolvaptan 1% granules. If the investigator or subinvestigator judges that there are an 
excessive aquaresis or safety concerns of subjects, the dose may be reduced (see 
Section 3.2.3). For subjects who need to continue treatment after 3-day administration at 
the dose decided individually, extended treatment for up to 4 days is allowed if the aim is 
to collect data on administration for up to 7 days and if the investigator or subinvestigator 
considers the safety of subjects to be ensured (including ensuring safety by dose 
reduction) (see Section 3.2.4). The dose, the date and time of administration, and the 
reason for dose reduction (for dose reduction, see Section 3.2.3) will be recorded in a 
source document and a case report form (CRF). 
3.2.2 
Increasing the Dose of Tolvaptan 
Tolvaptan should be administered according to the following procedure. Daily urine 
volume should be assessed as “insufficient increase in urine volume” when it is less than 
150% of that for the pretreatment observation period (1 day before start of tolvaptan 
administration), and “sufficient increase in urine volume” when it is at least 150%. 
1) Tolvaptan administration will be started at 0.05 mg/kg/day, and administration at 
0.05 mg/kg/day will be continued for 2 days. 
2) For subjects with sufficient increase in urine volume on Day 1 or Day 2 of 
treatment, administration at 0.05 mg/kg/day will be continued for 3 days. For 
subjects with an insufficient increase in urine volume on Day 1 and Day 2 of 
treatment, the dose will be increased to 0.15 mg/kg/day on Day 3. 
3) If a sufficient increase in urine volume is observed following 2-day administration 
at 0.15 mg/kg/day on Day 3 or Day 4 of the treatment period, administration at 
0.15 mg/kg/day will be continued for 3 days. For subjects with an insufficient 

 
 
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increase in urine volume on Day 3 and Day 4 of the treatment period, the dose 
will be increased to 0.3 mg/kg/day on Day 5. 
4) If a sufficient increase in urine volume is observed following 2-day administration 
at 0.3 mg/kg/day on Day 5 or Day 6 of the treatment period, administration at 
0.3 mg/kg/day will be continued for 3 days. For subjects with an insufficient 
increase in urine volume on Day 5 and Day 6 of the treatment period, the dose 
will be increased to 0.5 mg/kg/day on Day 7, and administration at 0.5 mg/kg/day 
will be continued for 3 days. 
 
3.2.3 
Reducing the Dose of Tolvaptan 
If symptoms associated with excessive aquaresis such as persistent sensation of thirst, 
dehydration, and hypernatremia are observed or there are safety concerns in subjects, at a 
discretion of the investigator or subinvestigator, the dose may be reduced only to the next 
lower dose. In that case, however, the dose of conventional diuretics should not be 
changed. If the dose of tolvaptan needs to be reduced before completion of 3-day 
administration at the same dose, it should be administered at the reduced dose for 3 days. 
If the dose of tolvaptan needs to be further reduced after dose reduction to the next lower 
dose, the subject will be judged to have a problem with tolerability to tolvaptan and 
should be withdrawn from the trial. 
3.2.4 
Extended Treatment With Tolvaptan 
Patterns of treatment with tolvaptan including extended treatment are shown in 
Figure 3.2.4-1. If the investigator or subinvestigator judges that the safety of subjects can 
continue to be ensured (including ensuring safety by dose reduction) after 3-day 
administration at the dose decided according to the specification for increasing the dose 
of tolvaptan (see Section 3.2.2), administration at that dose may be continued for up to 4 
days (for up to 7 days in total). 
In the case of an extended treatment with tolvaptan at reduced dose, the total number of 
administration days should be up to 7 days, which consists of “the days of administration 
at the dose just before the dose requiring reduction”, “the days of administration at the 
dose requiring reduction” and “the days of administration at the dose reduced to the next 
lower dose” (see examples of dose reduction in Figure 3.2.4-1). 
 

 
 
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Figure 3.2.4-1 
Patterns of Treatment With Tolvaptan Including Extended 
Treatment 
In principle, tolvaptan will be administered while increasing its dose every 2 days, and then, 
administered at the dose decided for each individual subject for 3 days. If the dose needs to be reduced 
before completion of 3-day administration, the dose may be reduced only once. The reduced dose should 
be regarded as the dose decided for each individual subject, and tolvaptan should be administered at the 
dose for 3 days. The duration of extended treatment at the reduced dose will be limited. 
 
3.2.5 
Treatment Period 
According to the patterns of treatment with tolvaptan, the duration of treatment period 
will be 3 days at the shortest, and 13 days at the longest if tolvaptan is administered until 
the dose is increased to 0.5 mg/kg/day, at 0.5 mg/kg/day for 3 days, and at 0.5 mg/kg/day 
for additional 4 days. 
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.05
0.05
0.05
0.05
0.05
0.05
0.05
Unit: mg/kg/day
Treatment Period
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
0.3
0.15
0.15
0.15
0.15
0.15
0.15
0.05
0.05
0.15
0.15
0.05
0.05
0.05
0.05
0.05
Dose-reduction example 1: The dose was increased to 0.3 mg/kg/day, but needed to be reduced on
the first day of administration at the increased dose.
Then, administration at 0.15 mg/kg/day was continued for 3 days.
In this case, administration at 0.15 mg/kg/day can be continued for 1 day only.
Dose-reduction example 2: The dose was increased to 0.15 mg/kg/day, but needed to be reduced
on the second day of administration at the increased dose.
Then, administration at 0.05 mg/kg/day was continued for 3 days.
In this case, administration at the reduced dose (0.05 mg/kg/day) cannot be continued.
Basic treatment pattern
Increasing tolvaptan dose (for dose increase procedure, see Section 3.2.2)
Reducing tolvaptan dose (for dose reduction procedure, see Section 3.2.3)
Treatment with tolvaptan may be further continued for up to 4 days (for up to 7 days in
total), if possible.
For extended treatment, see Section 3.2.4.
In the case of dose reduction, the number
of administration days should be up to 7
days, which consists of “the days of
administration at the dose (0.15) just before
the dose requiring reduction (0.3)”, “the
days of administration at the dose requiring
reduction (0.3)”, and “the days of
administration at the dose reduced to the
next lower level (0.15)” (see Section 3.2.4).
(Unit: mg/kg/day)
In the case of dose reduction, the number
of administration days should be up to 7
days, which consists of “the days of
administration at the dose (0.05) just before
the dose requiring reduction (0.15)”, “the
days of administration at the dose requiring
reduction (0.15)”, and “the days of
administration at the dose reduced to the
next lower level (0.05)” (see Section 3.2.4).
(Unit: mg/kg/day)
Administration period for extended treatment with tolvaptan at reduced dose

 
 
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[Rationale for the Treatment Period] 
In a phase 3 trial in adult cardiac edema patients in Japan (Trial 156-06-002), a 
significant decrease in body weight (−1.27 kg) was seen even on Day 3 although its 
degree was smaller than that on Day 7 (−1.67 kg). In the retrospective study in pediatric 
heart failure patients in Japan,2 an increase in urine volume and a decrease in body 
weight reached almost a plateau on Day 3 of treatment. Therefore, 3-day administration 
of tolvaptan is considered to be able to provide adequate data to evaluate its efficacy. In 
addition, it is considered that the efficacy evaluation needs to be performed for as short a 
time as possible because the duration to fix the dose and regimen of concomitant drugs 
cannot be prolonged. In view of this, administration for 3 days in the shortest is 
appropriate. 
In 2 phase 3 trials in adult cardiac edema patients in Japan (Trials 156-06-002 and 
156-06-006), the safety and efficacy of 7-day administration, and the safety of 14-day 
administration were confirmed, respectively. Therefore, it is considered to be appropriate 
to allow extended treatment with tolvaptan for 7 days which may result in administration 
for up to 13 days including the ascending dose period. 
3.2.6 
Hospitalization 
Subjects will be hospitalized prior to the evening meal on 3 days before start of tolvaptan 
administration until completion of an examination 2 days after final administration. The 
investigator or subinvestigator will record the dates of hospitalization and discharge for 
each individual subject in a source document and a CRF. 
 
3.3 
Trial Population 
Pediatric heart failure patients age 6 months to less than 15 years with volume overload 
despite having received conventional diuretic therapy 
“Pediatric heart failure patients with volume overload despite having received 
conventional diuretic therapy” are defined as patients with volume overload despite 
having received any of the following diuretic therapies 1) in whom sufficient effects 
cannot be expected even if the dose of the diuretics is increased, or 2) in whom the 
investigator or subinvestigator judges that increasing the dose of the diuretics is difficult 
due to concerns regarding electrolyte abnormalities or other side effects. 

 
 
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 Furosemide (oral administration) ≥0.5 mg/kg/day 
Azosemide 30 mg and torasemide 4 mg will be calculated as equivalent to furosemide 
20 mg. 
 Hydrochlorothiazide ≥2 mg/kg/day 
 Trichlormethiazide ≥0.05 mg/kg/day 
 Spironolactone ≥1 mg/kg/day 
 
3.3.1 
Number of Subjects and Description of Population 
The subject population includes male or female pediatric heart failure patients with 
volume overload despite having received conventional diuretic therapy whose age is 6 
months to less than 15 years at the time of informed consent by a legal representative. 
The planned number of subjects for receiving tolvaptan is set at 60. 
According to a separately specified procedure, target patients will be divided into 3 age 
groups (6 months to less than 2 years, 2 years to less than 7 years, and 7 years to less than 
15 years). Patients in the old age group (7 years to less than 15 years) will be enrolled at 
first, and a medical advisor will confirm that there is no safety problem in the group when 
the first 6 subjects complete administration. The enrollment of patients in the middle age 
group (2 years to less than 7 years) will be started after that (while the enrollment of 
patients in the old age group will be continued). A medical advisor will confirm that there 
is no safety problem in the middle age group (2 years to less than 7 years) when the first 
6 subjects in the group complete administration, and then, the enrollment of patients in 
the young age group (6 months to less than 2 years) will be started. The number of 
patients to be enrolled is up to 24 each for the old age group and the middle age group. 
For patients in the young age group (6 months to less than 2 years), a medical advisor 
will confirm the safety when the first 3 subjects in the group complete administration, 
and then the subsequent enrollment will be started. Underdeveloped patients who are 
classified into the middle or old age group but weigh less than half the ideal body weight3 
for children at the lower limit of age in each group (2 or 7 years) will be enrolled after 
start of administration for subjects in the next younger age group. 
3.3.2 
Subject Selection and Numbering 
A subject identifier (subject ID) [site number (3 digits) + S + serial number within the 
site (5 digits)] will be assigned to each subject for whom a legal representative has given 
informed consent. The [site number (3 digits)] will be designated by the sponsor. The 
[serial number within the site (5 digits)] will be assigned from 00001, in the order of 

 
 
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informed consent obtained, within each trial site. The trial site will prepare and retain a 
list of all subjects for whom a legal representative has given informed consent with their 
subject identifiers. 
 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Written informed consent will be freely obtained from all subjects’ legal representatives 
(their guardians or legally acceptable representatives, as applicable for laws). If possible, 
assent (agreement from pediatric subjects who are not subject to legal regulations) will 
also be obtained from participating subjects themselves. Consent will be documented on 
a written informed consent form (ICF), and assent will be documented on a written 
informed assent form (IAF). The ICF and IAF will be approved by the same institutional 
review board (IRB) that approves this protocol. 
Each ICF will comply with the International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline4 and local regulatory requirements. 
Investigators or subinvestigator may discuss trial availability and the possibility for entry 
with the legal representative without first obtaining consent. However, informed consent 
must be obtained from the legal representative 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). 
Legal representatives and 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 legal representative by the investigator or subinvestigator, the 
IRB approved written ICF will be signed and dated by both the legal representative and 
the person obtaining consent (investigator or subinvestigator). For obtaining assent from 
the subject himself/herself, full explanation will be given to the potential subject in 
layman’s language according to his/her age, and then, the IRB approved written IAF will 
be signed and dated by both the subject himself/herself and the person obtaining assent 
(investigator or subinvestigator). If a clinical trial associate has provided a supplemental 
explanation, the IRB approved written ICF and IAF will be signed and dated by the 

 
 
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clinical trial associate. The legal representative will receive a copy of the signed ICF and 
IAF; the originals shall be kept on file by the investigator or subinvestigator. 
Legal representatives may be asked to sign additional ICFs if the protocol is amended to 
significantly add or change procedures. 
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. 
Male or female patients age 6 months to less than 15 years at the time of informed consent by a 
legal representative 
2. 
Patients with volume overload despite having received any of the following diuretic therapies in 
whom sufficient effects cannot be expected even if the dose of the diuretics is increased or in whom 
the investigator or subinvestigator judges that increasing the dose of the diuretics is difficult due to 
concerns regarding electrolyte abnormalities or other side effects 
 
Furosemide (oral administration) ≥0.5 mg/kg/day 
Azosemide 30 mg and torasemide 4 mg will be calculated as equivalent to furosemide 20 mg. 
 
Hydrochlorothiazide ≥2 mg/kg/day 
 
Trichlormethiazide ≥0.05 mg/kg/day 
 
Spironolactone ≥1 mg/kg/day 
3. 
Patients capable of complaining of thirst. Patients unable to complain of thirst due to their young 
age can also be enrolled in the trial if strict management of fluid intake and excretion is conducted 
(frequent monitoring during the 8 hours after start of tolvaptan administration and at the time of 
dose-increase, and at least as frequent as every 8 hours at other times). However, even if such fluid 
management is possible, patients in whom the investigator or subinvestigator judges that tolvaptan 
cannot be safely administered are to be excluded. 
4. 
Patients who can be hospitalized from at least 3 days before start of tolvaptan administration until 2 
days after final administration 
 
[Rationale for the Inclusion Criteria] 
1) 
In consideration of trial conduct and the fact that many patients, even at the age of less than 1 year, 
need tolvaptan therapy, the lower limit of age is determined to be 6 months. As adolescent patients 
may also require tolvaptan therapy, the upper limit of age is determined to be less than 15 years as 
specified in the package insert of tolvaptan. 
2) 
The criterion is set based on the clinical position of tolvaptan. 
3) 
When tolvaptan therapy produces an excessive diuretic effect and significantly disrupts the balance 
between fluid intake and excretion, a serum or blood sodium concentration may be rapidly increased. 
Therefore, this trial can be safely conducted by strictly managing the fluid balance while monitoring 
serum or blood sodium concentration for patients unable to complain of thirst due to their young age, 
and taking appropriate actions such as the use of hypotonic solution as needed. The criterion is set 
from this perspective. 
4) 
The criterion is set to evaluate the efficacy and safety in this trial. 
 

 
 
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3.4.3 
Exclusion Criteria 
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1. 
Subjects’ legal representatives must agree the restriction on medications specified in 
Section 4. 
Table 3.4.3-1 
Exclusion Criteria 
1. 
Patients whose volume overload status shows improvement during the screening period or 
pretreatment observation period 
2. 
Patients who are unable to drink fluid (including patients who are unable to sense thirst) 
3. 
Patients whose circulatory blood flow is suspected to be decreased 
4. 
Patients with an assisted circulation apparatus 
5. 
Patients with hypernatremia (serum or blood sodium concentration exceeding 145 mEq/L) 
6. 
Patients with serum or blood potassium concentration exceeding the upper limit of the reference 
range for their age and gender 
7. 
Patients with a history or concurrent condition of liver impairment, including those with aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 times the upper limit of the 
reference range for their age and gender at the time of the screening examination or during the 
pretreatment observation period 
8. 
Patients with serum creatinine corresponding to Stage 3 or higher in the CKD Stage Assessment 
Using Serum Creatinine Level (mg/dL) Chart5 in the renal function assessment at the time of 
diagnosis of pediatric chronic kidney disease (pediatric CKD) 
9. 
Patients with anuria 
10. 
Patients with urinary excretion disorders due to urinary stenosis, urinary calculus, tumor, etc 
11. 
Patients who have participated in any other trials within 30 days prior to informed consent by a 
legal representative 
12. 
Patients who have received tolvaptan therapy before 
13. 
Female patients who are breastfeeding or who tests positive in pregnancy test prior to tolvaptan 
administration 
14. 
Female patients who are pregnant or suspected of being pregnant, or patients who cannot agree to 
remain fully abstinent during the trial and for 30 days after the last dose of IMP 
15. 
Breastfed patients (excluding those patients whose fluid intake can be measured by expressed 
breast milk or other ways, and whose mother does not use any of prohibited/restricted concomitant 
medications from 1 week before informed consent to completion of an examination 2 days after 
final administration) 
16. 
Patients who are judged to be ineligible to participate in this trial by the investigator or 
subinvestigator. 
 
[Rationale for the Inclusion Criteria] 
1) 
The criterion is set because the efficacy evaluation may be affected. 
2) 
The criterion is set because tolvaptan therapy for such patients is contraindicated in the package insert 
of Samsca®. 
3) 
The criterion is set because treatment through excessive diuresis is unfavorable. 
4) 
The criterion is set because the evaluation of efficacy and safety may be affected. 
5) 
The criterion is set because tolvaptan therapy for such patients is contraindicated in the package insert 
of Samsca. 
6) to 8) The criteria are set because it is difficult to ensure the safety of the patients during the trial. 
9) 
The criterion is set because tolvaptan therapy for such patients is contraindicated in the package insert 
of Samsca. 
10) The criterion is set because it is difficult to ensure the safety of such patients during the trial or 

 
 
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because enrollment of such patients is considered to be inappropriate. 
11) The criterion is set because the evaluation of efficacy and safety may be affected. 
12) The criterion is set because the evaluation of efficacy may be affected. 
13) to 14) The criteria are set because tolvaptan has been shown to be teratogenic and embryo-fetal lethal 
(in rabbits), and excreted into milk (in rats). 
15) The criterion is set because the control of drugs in breast milk and the measurement of fluid intake 
cannot be performed in such patients. 
16) The criterion is set because the evaluation of efficacy and safety may be affected. 
 
3.5 
Endpoints 
3.5.1 
Primary Endpoint 
The percentage of subjects who satisfy the following condition: 
 Body weight on the day after the third day of treatment with tolvaptan at the 
evaluation dose (see Section 7.4) is decreased by 1.7% or more from the weight 
measured before breakfast on the first day of the treatment period 
However, mean daily urine volume for the 3 days of treatment with tolvaptan at the 
evaluation dose must be higher than the daily urine volume for the pretreatment 
observation period. For subjects who discontinued treatment with tolvaptan, mean daily 
urine volume up until the time of discontinuation must be higher than the daily urine 
volume for the pretreatment observation period. 
<Rationale for the Primary Endpoint> 
Body weight in heart failure patients is considered to reflect change in systemic volume 
overload, and it is therefore regarded as a general index to grasp volume overload status 
in edematous diseases. Tolvaptan was approved based on the results of trials conducted 
during its clinical development in adult heart failure patients with volume overload, 
where body weight was set as a primary efficacy endpoint. In view of the above, body 
weight is also employed as a safety endpoint in this trial. An increase in daily urine 
volume is set to confirm that a decrease in body weight is brought by the aquaretic effect 
of tolvaptan therapy. 
3.5.2 
Secondary Endpoints 
 Body weight 
 Edematous symptoms (edema [lower limbs, eyelids, etc], dyspnea, jugular venous 
distension, pulmonary congestion, cardiothoracic ratio, respiration rate at rest, pulse 
rate, and pleural effusion), central venous pressure (only subjects with central venous 
catheterization), and retention of pericardial effusion (only subjects requiring 
echocardiography to confirm retention of pericardial effusion prior to tolvaptan 
administration) 

 
 
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 Daily urine volume 
 
<Rationale for the Secondary Endpoints> 
In this trial, the degree of improvement in each edematous symptom is also set as an 
efficacy endpoint. Target edematous symptoms include edema (lower limbs, etc), jugular 
venous distension, pulmonary congestion, and cardiothoracic ratio, which were assessed 
in tolvaptan trials during its clinical development in adult heart failure patients with 
volume overload. As a particularly essential item for pediatric heart failure patients, 
dyspnea, respiration rate at rest, pulse rate, pleural effusion, central venous pressure, and 
retention of pericardial effusion will also be assessed in this trial. 
An increase in urine volume is an index reflecting the pharmacological action of 
tolvaptan. Body weight, which is set as an efficacy endpoint, may be affected by food 
intake, vomiting, excretion, or other factors. Therefore, daily urine volume is included in 
the efficacy endpoints to confirm that a decrease in body weight is caused by increasing 
the excretion of free water, the pharmacological action of tolvaptan. 
3.6 
Measures to Minimize/Avoid Bias 
As this is an uncontrolled trial in one active treatment group, blinding and randomization 
are not performed. 
3.7 
Trial Procedures 
Basic trial assessment schedule is shown in Table 3.7-1. See Section 3.7.1.4 for the 
assessment schedule when extending treatment with tolvaptan at the dose decided for 
each individual subject from the fourth day, and see Section 3.7.1.5 for the assessment 
schedule when extending treatment with tolvaptan at a reduced dose. 
 

 
 
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Table 3.7-1 
Basic Assessment Schedule Without Reduction of Dose or Extension of Treatment 
 
Screening
Follow-up
Withdrawal
Day -7 to -3
Before Start of
Treatment
Day -3
Before Start
of Treatment
Day -2
Before
Start of
Treatment
Day -1
Before Start
of
Treatment
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day After
Final
Administration
2 Days After
Final
Admnistration
5 to 7 Days After
Final
Administration
At Withdrawal
Informed Consent
□
Subject Enrollment
□
IMP Administration









Body Weight
□
○
○
○
○
○
○
○
○
○
○
○
○
□
□
Vital sign (Blood Pressure, Pulse
Rate, Body Temperature)
□
□
□
□
□
□
□
□
□
□
□
□
□
□
□
12-Lead ECG
□
□
□
LaboratoryTests
□
○
○
○
○
○
○
□
□
Serum/Blood Sodicum
concentration
□
○
○▼▲
○
○▼a▲a
○
○▼a▲a
○
○▼a▲a
○
○
○
□
□
Serum/Blood Potassium
concentration
□
○
○
○
○
○
○
○
○
○
○
○
□
□
Serum Osmolality
○
○
○
○
○
○
□
□
Plasma AVP Concentration (only
subjects for whom sample is
available)
○
○
Daily Urine Volume and Fluid
Intake, Urine Sodium and
Potassium Excretions, and Urine
Osmolalityb
Plasma Drug Concentrationc
○d ●d■d
○d ●d■d
○d ●d■d
○d ●d■d
○
□
Edematous Symptoms
□
□
□
□e
□e
□e
□e
□e
□e
□e
□e
□e
□
□
□
Chest X-ray
(Pulmonary Congestion,
Cardiacthoracic Ratio, Pleural
Effusion)
□
Pregnancy Test (only for female
subjects who have begun
menstruation)
□
Adverse Events
IMP Compliance
□
□
□
□
□
□
□
□
□
□
Concomittant Drugs and Therapies
□
□
□
□
□
□
□
□
□
□
□
□
□
□
□
□
□
□
□
Treatment Period
Pretreatment Obsertvation Period

 
 
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Assessments should be performed according to the schedules for Days 1 to 9 until completion of 3-day administration at the dose decided for each individual 
subject, and the schedules for Day After Final Administration and subsequent days after completion of 3-day administration at the dose decided for each 
individual subject. 
The schedule presented in Section 3.7.1.5 Extended Treatment With Tolvaptan at Reduced Dose will be followed when the dose needs to be reduced, and the 
schedule presented in Section 3.7.1.4 Extended Treatment With Tolvaptan at Dose Decided for Each Individual Subject From Fourth Day will be followed 
when treatment is extended after completion of 3-day administration at the dose decided for each individual subject. 
○ = Before breakfast; ◊ = After breakfast; □ = At a feasible time; ● = At 2 to 4 hours postdose; ▼ = At 4 to 6 hours postdose; ▲ = At 8 to 12 hours 
postdose; ■ = At 10 to 14 hours postdose. 
aTo be measured at the time of dose increase. 
bTo be measured up until the morning of the day after final IMP administration. 
cThe blood collection for measurement of plasma drug concentration specified for before breakfast (○) may be performed after breakfast as long as it is 
before IMP administration. 
dOnly on the third day of administration at 0.05, 0.15, 0.3, or 0.5 mg/kg/day. 
eAfter IMP administration. 
 

 
 
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3.7.1 
Schedule of Assessments 
3.7.1.1 
Screening Period (7 to 3 Days Before Start of Tolvaptan 
Administration) 
After obtaining informed consent from the legal representative, the investigator or 
subinvestigator will assign a subject identifier to the subject according to Section 3.3.2, 
and record the date of informed consent and the subject identifier in a source document 
and a CRF. 
The investigator or subinvestigator will perform the following examinations and 
investigations, and confirm that the subject meets all of the inclusion criteria and none of 
the exclusion criteria to record the result of confirmation in a source document and a CRF. 
1) Investigation of subject background 
 Birth date 
 Gender 
 Height 
 Race 
 Complication 
 Medical history 
 Etiology of heart failure 
2) Examinations and assessments 
 Concomitant drugs and therapies 
 Body weight 
 Vital signs 
 Laboratory tests 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Edematous symptoms 
 Pregnancy test (urine human chorionic gonadotropin [hCG] test): Only for 
female subjects who have begun menstruation 
 Adverse events 
 
3.7.1.2 
Pretreatment Observation Period 
3.7.1.2.1 
Pretreatment Observation Period (3 Days Before Start of 
Tolvaptan Administration) 
The investigator or subinvestigator will admit the subject to the trial site before evening 
meal to perform the following investigations. 

 
 
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 Concomitant drugs and therapies 
 Adverse events 
 
3.7.1.2.2 
Pretreatment Observation Period (2 Days Before Start of 
Tolvaptan Administration) 
The investigator or subinvestigator will perform the following procedures. 
1) Before breakfast 
 Body weight 
2) At a feasible time 
 12-lead electrocardiogram (ECG) (at any time 1 day before start of tolvaptan 
administration) 
 Chest x-ray (at any time 1 day before start of tolvaptan administration) 
 Edematous symptoms 
 Concomitant drugs and therapies 
 Adverse events 
 
3.7.1.2.3 
Pretreatment Observation Period (1 Day Before Start of 
Tolvaptan Administration) 
The investigator or subinvestigator will perform the following procedures. 
The investigator or subinvestigator will confirm that the subject does not meet Exclusion 
Criteria 1, and record the result of confirmation in a source document and a CRF. 
1) Before breakfast 
 Body weight 
 Laboratory tests 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
 Plasma AVP concentration (only subjects from whom samples are available) 
2) Approximately 24 hours before the scheduled time of first tolvaptan 
administration 
The subject will be instructed to completely discharge the urine immediately after 
breakfast. Urine collection and fluid intake measurement will be started to assess the 
following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 

 
 
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 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
3) At a feasible time 
 Subject enrollment 
 Vital signs 
 12-lead ECG (at any time 2 day before start of tolvaptan administration) 
 Chest x-ray (at any time 2 day before start of tolvaptan administration) 
 Edematous symptoms 
 Concomitant drugs and therapies 
 Adverse events 
 
3.7.1.3 
Treatment Period 
Procedures will be conducted according to the schedules specified in Section 3.7.1.3.1 to 
Section 3.7.1.3.9 until completion of 3-day administration at the dose decided for each 
individual subject, and the schedules specified in Section 3.7.1.3.10 and subsequent 
sections after completion of 3-day administration at the dose decided for each individual 
subject. If extending treatment at the dose decided for each individual subject from the 
fourth day, the schedule presented in Section 3.7.1.4 should be followed. 
If the dose needs to be reduced, the schedule presented in Section 3.7.1.5 should be 
followed. 
3.7.1.3.1 
Day 1 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 

 
 
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 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan 
(0.05 mg/kg/day) with water after breakfast. After administration, the change in 
serum or blood sodium concentration will be observed. If the change meets the 
following criteria, the investigator or subinvestigator should discontinue treatment 
with tolvaptan as specified in Section 3.8.3.1, and perform the withdrawal 
examination according to Section 3.7.1.6. 
 Serum or blood sodium concentration increased by ≥8 mEq/L from that 
immediately before tolvaptan administration, within 8 to 12 hours after 
administration 
 Serum or blood sodium concentration increased by ≥12 mEq/L from that 
immediately before tolvaptan administration, within 24 hours after 
administration 
 Serum or blood sodium concentration exceeding 145 mEq/L is observed 
during the treatment period 
3) 4 to 6 hours after tolvaptan administration 
 Serum or blood sodium concentration 
4) 8 to 12 hours after tolvaptan administration 
 Serum or blood sodium concentration 
5) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.3.2 
Day 2 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Laboratory tests 

 
 
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 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan 
(0.05 mg/kg/day) with water after breakfast. 
3) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.3.3 
Day 3 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Plasma drug concentration (on the third day of administration at 
0.05 mg/kg/day) 
Assessment after breakfast is allowed if it is conducted prior to tolvaptan 
administration. 

 
 
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The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) 2 to 4 hours after tolvaptan administration (on the third day of administration at 
0.05 mg/kg/day) 
 Plasma drug concentration 
4) 4 to 6 hours after tolvaptan administration (at increased dose) 
 Serum or blood sodium concentration 
5) 8 to 12 hours after tolvaptan administration (at increased dose) 
 Serum or blood sodium concentration 
6) 10 to 14 hours after tolvaptan administration (on the third day of administration at 
0.05 mg/kg/day) 
 Plasma drug concentration 
7) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.3.4 
Day 4 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Laboratory tests 

 
 
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 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.3.5 
Day 5 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Plasma drug concentration (on the third day of administration at 
0.15 mg/kg/day) 
Assessment after breakfast is allowed if it is conducted prior to tolvaptan 
administration. 

 
 
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The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) 2 to 4 hours after tolvaptan administration (on the third day of administration at 
0.15 mg/kg/day) 
 Plasma drug concentration 
4) 4 to 6 hours after tolvaptan administration (at increased dose) 
 Serum or blood sodium concentration 
5) 8 to 12 hours after tolvaptan administration (at increased dose) 
 Serum or blood sodium concentration 
6) 10 to 14 hours after tolvaptan administration (on the third day of administration at 
0.15 mg/kg/day) 
 Plasma drug concentration 
7) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.3.6 
Day 6 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Laboratory tests 

 
 
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 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.3.7 
Day 7 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Plasma drug concentration (on the third day of administration at 
0.3 mg/kg/day) 
Assessment after breakfast is allowed if it is conducted prior to tolvaptan 
administration. 

 
 
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The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) 2 to 4 hours after tolvaptan administration (on the third day of administration at 
0.3 mg/kg/day) 
 Plasma drug concentration 
4) 4 to 6 hours after tolvaptan administration (at increased dose) 
 Serum or blood sodium concentration 
5) 8 to 12 hours after tolvaptan administration (at increased dose) 
 Serum or blood sodium concentration 
6) 10 to 14 hours after tolvaptan administration (on the third day of administration at 
0.3 mg/kg/day) 
 Plasma drug concentration 
7) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.3.8 
Day 8 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Laboratory tests 

 
 
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 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.3.9 
Day 9 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Plasma drug concentration (on the third day of administration at 
0.5 mg/kg/day) 
Assessment after breakfast is allowed if it is conducted prior to tolvaptan 
administration. 

 
 
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The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) 2 to 4 hours after tolvaptan administration 
 Plasma drug concentration (on the third day of administration at 
0.5 mg/kg/day) 
4) 10 to 14 hours after tolvaptan administration 
 Plasma drug concentration (on the third day of administration at 
0.5 mg/kg/day) 
5) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.3.10 
Day After Final Administration 
If administration at the dose decided for each individual subject is completed in 3 days, 
the investigator or subinvestigator will perform the following procedures on the day after 
final administration. 
1) Before breakfast 
 Body weight 
 Laboratory tests 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
 Plasma AVP concentration (only subjects from whom samples are available) 

 
 
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 Plasma drug concentration: Assessment after breakfast is allowed. 
2) At a feasible time 
 Vital signs 
 12-lead ECG 
 Edematous symptoms 
 Chest x-ray 
 Concomitant drugs and therapies 
 Adverse events 
 
3.7.1.3.11 
Two Days After Final Administration 
If administration at the dose decided for each individual subject is completed in 3 days, 
the investigator or subinvestigator will perform the following procedures 2 days after 
final administration. 
1) At a feasible time 
 Vital signs 
 Concomitant drugs and therapies 
 Adverse events 
 
3.7.1.4 
Extended Treatment With Tolvaptan at Dose Decided for Each 
Individual Subject From Fourth Day 
The schedules presented in Section 3.7.1.4.1 to Section 3.7.1.4.4 should be followed 
when extending treatment at the dose decided for each individual subject, and the 
schedules presented in Section 3.7.1.4.5 and subsequent sections should be followed after 
completion of extended treatment. 
If the dose needs to be reduced, the schedule presented in Section 3.7.1.5 should be 
followed. 
3.7.1.4.1 
Fourth Day of Administration at Dose Decided for Each 
Individual Subject 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and 
then, offer breakfast to the subject. 
 Body weight 
 Laboratory tests 

 
 
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 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
 Plasma AVP concentration (only subjects from whom samples are available) 
 Plasma drug concentration: Assessment after breakfast is allowed if it is 
conducted prior to tolvaptan administration. 
 
The investigator or subinvestigator will instruct the subject to completely 
discharge the urine immediately after breakfast, and start urine collection and 
fluid intake measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) At a feasible time 
 Vital signs 
 12-lead ECG 
 Edematous symptoms (after tolvaptan administration) 
 Chest x-ray 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.4.2 
Fifth Day of Administration at Dose Decided for Each 
Individual Subject 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Serum or blood sodium concentration 

 
 
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 Serum or blood potassium concentration 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.4.3 
Sixth Day of Administration at Dose Decided for Each 
Individual Subject 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Laboratory tests 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 

 
 
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 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.4.4 
Seventh Day of Administration at Dose Decided for Each 
Individual Subject 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 

 
 
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3) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.4.5 
Day After Final Administration in Extended Treatment 
The investigator or subinvestigator will perform the following procedures. 
1) Before breakfast 
 Body weight 
 Laboratory tests (Assessment will not be performed if it is completed on the 
previous day.) 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality (Assessment will not be performed if it is completed on the 
previous day.) 
2) At a feasible time 
 Vital signs 
 Edematous symptoms 
 Concomitant drugs and therapies 
 Adverse events 
 
3.7.1.4.6 
Two Days After Final Administration in Extended Treatment 
The investigator or subinvestigator will perform the following procedures. 
1) At a feasible time 
 Vital signs 
 Concomitant drugs and therapies 
 Adverse events 
 
3.7.1.5 
Extended Treatment With Tolvaptan at Reduced Dose 
The schedules presented in Section 3.7.1.5.1 to Section 3.7.1.5.4 should be followed 
when extending treatment at reduced dose, and the schedules presented in 
Section 3.7.1.5.5 and subsequent sections should be followed after completion of 
extended treatment. 

 
 
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3.7.1.5.1 
First Day of Administration at Reduced Dose 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Laboratory tests 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
 Plasma AVP concentration (on the day after the third day of administration at 
0.15, 0.3, or 0.5 mg/kg/day; only subjects from whom samples are available) 
 Plasma drug concentration (on the day after the third day of administration at 
0.15, 0.3, or 0.5 mg/kg/day): Assessment after breakfast is allowed if it is 
conducted prior to tolvaptan administration. 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) At a feasible time 
 Vital signs 
 12-lead ECG (on the day after the third day of administration at 0.15, 0.3, or 
0.5 mg/kg/day) 
 Edematous symptoms (after tolvaptan administration) 
 Chest x-ray (on the day after the third day of administration at 0.15, 0.3, or 
0.5 mg/kg/day) 
 Concomitant drugs and therapies 

 
 
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 IMP compliance 
 Adverse events 
 
3.7.1.5.2 
Second Day of Administration at Reduced Dose 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 
 Body weight 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.5.3 
Third Day of Administration at Reduced Dose 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 

 
 
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 Body weight 
 Laboratory tests 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Plasma drug concentration: Assessment after breakfast is allowed if it is 
conducted prior to tolvaptan administration. 
 Serum osmolality 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) 2 to 4 hours after tolvaptan administration 
 Plasma drug concentration 
4) 10 to 14 hours after tolvaptan administration 
 Plasma drug concentration 
5) At a feasible time 
 Vital signs 
 Edematous symptoms (after tolvaptan administration) 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.5.4 
Fourth Day of Administration at Reduced Dose 
The investigator or subinvestigator will perform the following procedures. 
1) Before tolvaptan administration 
The investigator or subinvestigator will perform the following examinations, and then, 
offer breakfast to the subject. 

 
 
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 Body weight 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration  
 Plasma AVP concentration (only subjects from whom samples are available) 
 Plasma drug concentration: Assessment after breakfast is allowed if it is 
conducted prior to tolvaptan administration. 
The investigator or subinvestigator will instruct the subject to completely discharge 
the urine immediately after breakfast, and start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urine sodium excretion 
 Urine potassium excretion 
 Urine osmolality 
2) Tolvaptan administration 
The investigator or subinvestigator will instruct the subject to take tolvaptan with 
water after breakfast according to Section 3.2. 
3) At a feasible time 
 Vital signs 
 12-lead ECG 
 Edematous symptoms (after tolvaptan administration) 
 Chest x-ray 
 Concomitant drugs and therapies 
 IMP compliance 
 Adverse events 
 
3.7.1.5.5 
Day After Final Administration in Extended Treatment at 
Reduced Dose 
The investigator or subinvestigator will perform the following procedures. 
1) Before breakfast 
 Body weight 
 Laboratory tests (Assessment will not be performed if it is completed on the 
previous day.) 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 

 
 
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 Serum osmolality (Assessment will not be performed if it is completed on the 
previous day.) 
 Plasma AVP concentration (on the day after the third day of administration at 
reduced dose; only subjects from whom samples are available) 
 Plasma drug concentration (on the day after the third day of administration at 
reduced dose) 
: Assessment after breakfast is allowed if it is conducted prior to tolvaptan 
administration. 
2) At a feasible time 
 Vital signs 
 12-lead ECG (on the day after the third day of administration at reduced dose) 
 Edematous symptoms 
 Chest x-ray (on the day after the third day of administration at reduced dose) 
 Concomitant drugs and therapies 
 Adverse events 
 
3.7.1.5.6 
Two Days After Final Administration in Extended Treatment 
at Reduced Dose 
The investigator or subinvestigator will perform the following procedures. 
1) At a feasible time 
 Vital signs 
 Concomitant drugs and therapies 
 Adverse events 
 
3.7.1.6 
Treatment Discontinuation 
When discontinuation of treatment with tolvaptan is deemed necessary according to the 
rules specified in Section 3.8.3.1, the investigator or subinvestigator will perform the 
following examinations or investigations. If the examination or investigation has been 
completed on the day of treatment discontinuation, it does not have to be repeated. If it is 
not feasible to perform all of the examinations, observations, and assessments at 
treatment discontinuation, because of the subject’s refusal or at the discretion of the 
investigator or subinvestigator (eg, in emergencies), only feasible ones should be 
performed. 
 Concomitant drugs and therapies 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 

 
 
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 Body weight 
 Laboratory tests 
 Serum osmolality 
 Plasma drug concentration (Assessment does not have to be repeated on the 
day of treatment discontinuation if it has been conducted after administration.) 
 Vital signs 
 12-lead ECG 
 Edematous symptoms 
 IMP compliance 
 Adverse events 
 
3.7.1.7 
Follow-up Period (5 to 7 Days After Final Tolvaptan 
Administration) 
The investigator or subinvestigator will perform the following procedures. 
1) At a feasible time 
 Body weight 
 Vital signs 
 12-lead ECG 
 Laboratory tests 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Serum osmolality 
 Edematous symptoms 
 Concomitant drugs and therapies 
 Adverse events 
 
3.7.2 
Efficacy Assessments 
3.7.2.1 
Body Weight 
A calibrated scale (an instrument which can measure body weight to the second decimal 
point by the kilogram) should be used to determine body weight while minimizing the 
influence of clothing, at about the same time before breakfast throughout the trial period. 
The date and time, and result of measurement (to the second decimal point by the 
kilogram) will be recorded in a source document and a CRF. The result should be 
rounded to 2 decimal places. 

 
 
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3.7.2.2 
Daily Urine Volume 
During the pretreatment observation period, daily urine volume will be measured for the 
time interval starting at urination (an instruction to urinate) after breakfast and ending at 
complete urination immediately before administration on the following day. After start of 
tolvaptan administration on the first day of the treatment period, daily urine volume will 
be determined for each time interval from the point after urination (an instruction to 
urinate) immediately before administration of the day to the point after urination (an 
instruction to urinate) immediately before administration on the following day. 
For diapered subjects whose urine volume is difficult to determine by urine collection, 
urine volume may be estimated from the difference in the weight of diaper between 
before and after use (the weight at 1 g should be converted to 1 mL). The procedure 
should be established with consideration of measurement time to minimize fluctuations. 
The method of urine volume measurement (urine collection, diaper, or both) should not 
be changed throughout the trial period. 
The status (measured/not measured), start date and time, and completion date and time of 
measurement, as well as daily urinary volume will be recorded in a source document and 
a CRF. 
3.7.2.3 
Edematous Symptoms (Edema [Lower Limbs, Eyelids, etc], 
Dyspnea, Jugular Venous Distension, Respiration Rate at Rest, 
and Pulse Rate) 
3.7.2.3.1 
Edema (Lower Limbs, Eyelids, etc) 
3.7.2.3.1.1 
Edema (Lower Limbs) 
In principle, the grade of edema at the tibial border or the acrotarsium will be assessed in 
the sitting position, according to Table 3.7.2.3.1.1-1. The date and time, and result of 
assessment will be recorded in a source document and a CRF. 
Table 3.7.2.3.1.1-1 
Criteria for Grading Lower Limb Edema 
 
Grade 
Criterion 
0 
None 
No pit observed 
1 
Mild 
Faint pit observed 
2 
Moderate 
Pit observed 
3 
Severe 
Easily recognizable edema 
 
3.7.2.3.1.2 
Edema (Eyelids) 
The presence/absence of eyelid edema will be assessed. The date and time, and result of 
assessment will be recorded in a source document and a CRF. 

 
 
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3.7.2.3.1.3 
Edema (Others) 
The same criteria as those for lower limb edema will be adopted to assess other edema. 
The same area of the body will be assessed before and after administration. The area, date 
and time, and result of assessment will be recorded in a source document and a CRF. 
3.7.2.3.2 
Dyspnea 
The presence/absence of dyspnea will be assessed. The date and time, and result of 
assessment will be recorded in a source document and a CRF. 
3.7.2.3.3 
Jugular Venous Distension 
The presence/absence of jugular venous distension will be visually assessed. The date 
and time, and result of assessment will be recorded in a source document and a CRF. 
3.7.2.3.4 
Respiration Rate at Rest 
Respiration rate at rest will be measured by auscultation using a stethoscope, or by 
observing respiratory movement of the thorax (up-and-down movement of the chest) 
(times/minute). The date and time, and result of measurement will be recorded in a source 
document and a CRF. 
3.7.2.3.5 
Pulse Rate 
A calibrated measuring instrument should be used to determine pulse rate after resting for 
at least 3 minutes. The status (measured/not measured), date and time, and result of 
measurement will be recorded in a source document and a CRF. 
3.7.2.4 
Chest X-ray (Pulmonary Congestion, Cardiothoracic Ratio, and 
Pleural Effusion) 
A calibrated instrument should be used to perform chest x-ray, and the date of chest x-ray 
will be recorded in a source document and a CRF. An obtained radiograph will be 
assessed for pulmonary congestion, cardiothoracic ratio, and pleural effusion as described 
below, and the result of assessment will be recorded in a source document and a CRF. 
3.7.2.4.1 
Pulmonary Congestion 
The grade of pulmonary congestion will be assessed according to Table 3.7.2.4.1-1, and 
the date and result of assessment will be recorded in a source document and a CRF. 

 
 
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Table 3.7.2.4.1-1 
Criteria for Grading Pulmonary Congestion 
 
Grade 
Criterion 
0 
None 
No congestion 
1 
Mild 
Pulmonary venous congestion 
2 
Moderate 
Interstitial pulmonary edema 
3 
Severe 
Alveolar pulmonary edema 
Modified from the criteria by Forrester JS, et al.6 
 
3.7.2.4.2 
Cardiothoracic Ratio 
Cardiothoracic ratio (%) will be measured, and the date and result of measurement will 
be recorded in a source document and a CRF. For the result of measurement, a value to 
the first decimal point should be recorded. 
3.7.2.4.3 
Pleural Effusion 
The presence/absence of pleural effusion will be assessed, and the date and result of 
assessment will be recorded in a source document and a CRF. 
3.7.2.5 
Central Venous Pressure (Only Subjects With Central Venous 
Catheterization) 
In subjects with central venous catheterization who can undergo measurement before and 
after tolvaptan administration, a calibrated instrument should be used to determine central 
venous pressure (mmHg) in the way specified by each trial site. The date and result of 
measurement will be recorded in a source document and a CRF. 
3.7.2.6 
Retention of Pericardial Effusion (Only Subjects Requiring 
Echocardiography) 
For subjects who have been found to have excessive retention of pericardial effusion by 
echocardiography before tolvaptan administration and have undergone echocardiography 
again after administration, a change in the degree of retention from that before 
administration (decrease, no change, or increase from that before administration) will be 
assessed. The date and result of assessment will be recorded in a source document and a 
CRF. A calibrated instrument should be used for echocardiography. 
3.7.3 
Safety Assessments 
3.7.3.1 
Adverse Events 
Refer to Section 5. 

 
 
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3.7.3.2 
Laboratory tests 
For laboratory tests, each trial site should use appropriate equipment and apparatuses 
with reliable precision, and follow the procedures specified by the site (measurement at 
the site). When measurement at the site is not feasible, samples may be sent to the 
contract research organization for clinical laboratory tests (hereafter, central laboratory) 
for measurement. The central laboratory will measure the following items according to 
the procedures specified by the laboratory, and report the result of measurement to the 
sponsor, and the investigator or subinvestigator. The status (with or without blood/urine 
sampling), the date and time of blood sampling, the date of urine sampling, and the result 
of measurement will be recorded in a source document and a CRF. The result of 
measurement by the specified central laboratory does not have to be recorded. 
The case where the subject cannot provide urine sample for some reason despite having 
received an instruction to urinate will not be regarded as a deviation, but the reason 
should be recorded in a CRF. To ensure the safety of the subject, a sample should be 
obtained at a different time or day. 
Unscheduled laboratory tests, if required at the occurrence of AEs or for the follow-up of 
AEs, should be performed at each trial site. 
Table 3.7.3.2-1 
Clinical Laboratory Assessments 
Hematology: 
Hemoglobin 
Mean Corpuscular Hemoglobin Concentration 
Mean Corpuscular Volume  
Hematocrit 
Red Blood Cell count 
White Blood Cell count with differential 
Platelet count 
 
Urinalysis: 
Color 
Occult blood 
Glucose 
pH 
Protein 
Specific gravity 
 
 
Serum Chemistry: 
Alkaline Phosphatase 
ALT 
AST 
Bilirubin, total 
Blood Urea Nitrogen 
Uric acid 
Cholesterol 
Creatinine 
Gamma Glutamyl Transpeptidase 
Glucose 
Lactic Dehydrogenase  
Potassium 
Protein, total 
Albumin 
Sodium 
Triglycerides 
 
Additional Tests: 
Urine pregnancy test for all female subjects who 
have begun menstruation 
 
In all female subjects who have begun menstruation, a pregnancy test will be conducted 
at screening examination, and results must be available prior to tolvaptan administration. 

 
 
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3.7.3.3 
Vital signs 
3.7.3.3.1 
Body Temperature 
A calibrated thermometer should be used to determine body temperature. The status 
(measured/not measured), date and time, and result of measurement will be recorded in a 
source document and a CRF. For the result of measurement, a value to the first decimal 
point should be recorded. The result should be rounded to one decimal place. 
3.7.3.3.2 
Blood Pressure and Pulse Rate 
A calibrated measuring instrument should be used to determine blood pressure (systolic 
and diastolic) and pulse rate after resting for at least 3 minutes. The status (measured/not 
measured), date and time, and result of measurement will be recorded in a source 
document and a CRF. 
3.7.3.4 
12-lead Electrocardiogram 
A 12-lead ECG monitors sent by a central ECG measurement facility should be used to 
obtain an ECG according to the procedure specified by the laboratory. Based on the 
obtained ECG, the investigator or subinvestigator will record the status (measured/not 
measured) and date of 12-lead ECG measurement, and the result of assessment (normal 
or abnormal) in a source document and a CRF. An abnormal finding should be described 
in the source document and the CRF. The ECG will be sent to the central ECG 
measurement facility to measure heart rate, and PR, RR, QRS, QT, and QTc (QTcB, 
QTcF) intervals. The measurement report for the ECG will be sent to the investigator or 
subinvestigator, and the sponsor. The investigator or subinvestigator will refer to the 
measurement report to review the result of 12-lead ECG assessment, and sign and date 
the measurement report. For the measurement report, an electronic file submitted to the 
sponsor by the central ECG measurement facility is regarded as a source document, and 
the entry of the result in the CRF is unnecessary. 
3.7.3.5 
Pregnancy Test 
1) Subjects 
All female subjects who have begun menstruation at the time of pregnancy test will 
undergo the pregnancy test. Subjects with a history of hysterectomy or bilateral 
ovariectomy are regarded as women of nonchild-bearing potential, and do not have to 
undergo the pregnancy test. 

 
 
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2) Procedure 
Each trial site should use a pregnancy test reagent provided by the sponsor to perform 
urine hCG test in female subjects of child-bearing potential (see Section 5.5). If the 
result of test unclear, urine hCG test should be repeated. The investigator or 
subinvestigator will review the result of test, and record the status, date, and result 
(positive or negative) of test in a source document and a CRF. For a subject who is 
urine hCG test positive and suspected to be pregnant by the investigator or 
subinvestigator, treatment should be discontinued according to the rules specified in 
Section 5.5. 
3.7.4 
Pharmacokinetic/Pharmacodynamic Assessments 
3.7.4.1 
Pharmacokinetic Assessments 
3.7.4.1.1 
Pharmacokinetic Blood Samples 
1)  Time points of blood sampling (see Section 3.7.1.5 for time points in treatment at 
reduced dose) 
Before administration, and 2 to 4, 10 to 14, and approximately 24 hours after 
administration on the third day of treatment with tolvaptan at 0.05, 0.15, 0.3, or 
0.5 mg/kg/day. 
2) Procedures for blood sampling and measurement 
At time points shown in Section 3.7.4.1.1 1) and Table 3.7-1, a pharmacokinetic 
blood sample will be collected in a blood-collecting tube containing heparin sodium 
through an indwelling catheter or direct venipuncture. Cases where the subject cannot 
provide a blood sample for some reason will not be regarded as a deviation. The 
status (collected/not collected), and exact date and time of collecting a 
pharmacokinetic blood sample will be recorded in a CRF. 
All samples will be shipped to the bioanalytical laboratory shown in Appendix 1 to 
determine the plasma concentrations of OPC-41061 (tolvaptan), DM-4103, and 
DM-4107 according to an established procedure. Detailed handling and shipping 
instructions are provided in Appendix 1. 
3) Rationale for the time points of blood sampling 
To determine the pharmacokinetics of tolvaptan in pediatric heart failure patients, 
data on the plasma concentrations of OPC-41061 and its metabolites (DM-4103 and 
DM-4107) will be collected. For the time points of blood sampling, a trial in adult 
CHF patients (Trial 156-06-004) was referred to. As a result of consideration, a total 
of 4 time points (before administration, at around peak time [2-4 hours after 

 
 
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administration], and at times in an elimination phase [10-14 hours and 24 hours after 
administration]) are set so that the pharmacokinetic parameters of OPC-41061 can be 
determined by population pharmacokinetic analysis which will be separately 
conducted. 
3.7.4.2 
Pharmacodynamic Assessments 
3.7.4.2.1 
Daily fluid intake 
At the same interval as that for measurement of daily urine volume, daily fluid intake 
(beverages [eg, juice, milk, tea], water, and transfusion, etc) will be determined. During 
the pretreatment observation period, daily fluid intake will be measured for the time 
interval starting at an instruction to urinate after breakfast and ending at complete 
urination immediately before administration on the following day. After start of tolvaptan 
administration on the first day of the treatment period, daily fluid intake will be 
determined for each time interval from the point after complete urination immediately 
before administration of the day to the point after complete urination immediately before 
administration on the following day. 
The status (measured/not measured), start date and time, and completion date and time of 
measurement, as well as daily fluid intake will be recorded in a source document and a 
CRF. Water the subject drinks with tolvaptan will be included in the fluid intake after 
administration. 
3.7.4.2.2 
Daily Fluid Balance 
Daily fluid balance will be calculated by subtracting “daily urine volume” from “daily 
fluid intake”. Daily fluid balance will be calculated by the sponsor, and the entry of daily 
fluid balance in a CRF is unnecessary. 
3.7.4.2.3 
Serum Osmolality 
For laboratory tests, each trial site should use appropriate equipment and apparatuses 
with reliable precision, and follow the procedures specified by the site (measurement at 
the site). When measurement at the site is not feasible, samples may be sent to the 
specified central laboratory for measurement. The central laboratory will perform 
measurement according to the procedures specified by the laboratory, and report the 
result of measurement to the sponsor and the investigator or subinvestigator. Serum 
osmolality does not necessarily have to be measured if its measurement is difficult due to 
the volume of collected blood or other problems. The status (collected/not collected) and 
date of blood sampling, and the result of measurement will be recorded in a source 

 
 
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document and a CRF. The result of measurement by the specified central laboratory does 
not have to be recorded. 
3.7.4.2.4 
Serum or Blood Sodium Concentration 
For laboratory tests, each trial site should use appropriate equipment and apparatuses 
with reliable precision, and follow the procedures specified by the site (measurement at 
the site). When measurement at the site is not feasible, samples may be sent to the 
specified central laboratory for measurement. In that case, however, the same 
measurement procedure should be followed for each subject. The status (collected/not 
collected), and date and time of blood sampling, as well as the result of measurement will 
be recorded in a source document and a CRF. The result of measurement by the specified 
central laboratory does not have to be recorded. 
3.7.4.2.5 
Serum or Blood Potassium Concentration 
For laboratory tests, each trial site should use appropriate equipment and apparatuses 
with reliable precision, and follow the procedures specified by the site (measurement at 
the site). When measurement at the site is not feasible, samples may be sent to the 
specified central laboratory for measurement. In that case, however, the same 
measurement procedure should be followed for each subject. The status (collected/not 
collected), and date and time of blood sampling, as well as the result of measurement will 
be recorded in a source document and a CRF. The result of measurement by the specified 
central laboratory does not have to be recorded. 
3.7.4.2.6 
Urine Osmolality 
1) Urine sample processing (pretreatment observation period and treatment period) 
Approximately 5 mL aliquot of cumulative urine sample will be taken into a sample 
stock tube and stored in a refrigerator as needed. The date of sampling will be 
recorded in a source document. Daily urine volume should be determined before 
taking the aliquot. If spot urine sample has been obtained from a diapered subject, 
approximately 5 mL aliquot of the spot urine sample will be taken into a sample stock 
tube. For spot urine sample, urine volume at the interval of urine collection that the 
spot urine sample has been obtained, as well as the start and completion times of 
urine collection, will be recorded in a source document. 
Cases where the subject cannot provide a urine sample for some reason despite 
having received the instruction to urinate will not be regarded as a deviation, but the 
reason should be recorded in a CRF. 

 
 
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2) Measurement 
For laboratory tests, each trial site should use appropriate equipment and apparatuses 
with reliable precision, and follow the procedures specified by the site (measurement 
at the site). When measurement at the site is not feasible, samples may be sent to the 
specified central laboratory for measurement. The central laboratory will perform 
measurement according to the procedures specified by the laboratory, and report the 
result of measurement to the sponsor and the investigator or subinvestigator. The 
status (collected/not collected) and date of urine sampling, and the result of 
measurement will be recorded in a source document and a CRF. The result of 
measurement by the specified central laboratory does not have to be recorded. 
3.7.4.2.7 
Daily Urine Sodium Excretion 
1) Urine sample processing 
Approximately 5 mL aliquot of cumulative urine sample will be taken into a sample 
stock tube. The date of sampling will be recorded in a source document. Daily urine 
volume should be determined before taking the aliquot. If spot urine sample has been 
obtained from a diapered subject, approximately 5 mL aliquot of the spot urine 
sample will be taken into a sample stock tube. For spot urine sample, urine volume at 
the interval of urine collection that the spot urine sample has been obtained, as well as 
the start and completion times of urine collection, will be recorded in a source 
document. 
Cases where the subject cannot provide a urine sample for some reason despite 
having received the instruction to urinate will not be regarded as a deviation, but the 
reason should be recorded in a CRF. 
2) Measurement of urine sodium concentration 
For laboratory tests, each trial site should use appropriate equipment and apparatuses 
with reliable precision, and follow the procedures specified by the site (measurement 
at the site). When measurement at the site is not feasible, samples may be sent to the 
specified central laboratory for measurement. The central laboratory will perform 
measurement according to the procedures specified by the laboratory, and report the 
result of measurement to the sponsor and the investigator or subinvestigator. The 
status (collected/not collected) and date of urine sampling, and the result of 
measurement will be recorded in a source document and a CRF. The result of 
measurement by the specified central laboratory does not have to be recorded. 

 
 
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3) Calculation of urinary excretion 
Daily urinary excretion will be calculated by multiplying urinary concentration by 
daily urine volume. Urinary excretion will be calculated by the sponsor, and the entry 
of urinary excretion in a CRF is unnecessary. 
3.7.4.2.8 
Daily Urine Potassium Excretion 
1) Urine sample processing 
Approximately 5 mL aliquot of cumulative urine sample will be taken into a sample 
stock tube. The date of sampling will be recorded in a source document. Daily urine 
volume should be determined before taking the aliquot. If spot urine sample has been 
obtained from a diapered subject, approximately 5 mL aliquot of the spot urine 
sample will be taken into a sample stock tube. For spot urine sample, urine volume at 
the interval of urine collection that the spot urine sample has been obtained, as well as 
the start and completion times of urine collection, will be recorded in a source 
document. 
Cases where the subject cannot provide a urine sample for some reason despite 
having received the instruction to urinate will not be regarded as a deviation, but the 
reason should be recorded in a CRF. 
2) Measurement of urine potassium concentration 
For laboratory tests, each trial site should use appropriate equipment and apparatuses 
with reliable precision, and follow the procedures specified by the site (measurement 
at the site). When measurement at the site is not feasible, samples may be sent to the 
specified central laboratory for measurement. The central laboratory will perform 
measurement according to the procedures specified by the laboratory, and report the 
result of measurement to the sponsor and the investigator or subinvestigator. The 
status (collected/not collected) and date of urine sampling, and the result of 
measurement will be recorded in a source document and a CRF. The result of 
measurement by the specified central laboratory does not have to be recorded. 
3) Calculation of urinary excretion 
Daily urinary excretion will be calculated by multiplying urinary concentration by 
daily urine volume. Urinary excretion will be calculated by the sponsor, and the entry 
of urinary excretion in a CRF is unnecessary. 
3.7.4.2.9 
Plasma AVP Concentration 
Blood sample for measurement of plasma AVP concentration will be obtained, and the 
date of blood sampling will be recorded in a source document for the subject from whom 

 
 
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the sample is available. The sample will be shipped to the specified central laboratory for 
central measurement. The central laboratory will measure the above item according to the 
procedure specified by the laboratory, and report the result of measurement to the sponsor 
and the investigator or subinvestigator. The status (collected/not collected) and date of 
blood sampling, and the result of measurement will be recorded in a CRF. The result of 
measurement by the specified central laboratory does not have to be recorded. 
3.7.5 
End of Trial 
The end of trial date is defined as the date on which the last subject completes the trial. 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.8.1 
Entire Trial 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to the heads of the trial sites and regulatory authorities in accordance with 
regulatory requirements. 
3.8.2 
Individual Site Discontinuation 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB if judged to be necessary for medical, safety, regulatory, ethical or other reasons 
consistent with applicable laws, regulations, and GCP. The head of the trial site will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB at the 
site. 
3.8.3 
Individual Subject Discontinuation 
3.8.3.1 
Treatment Discontinuation 
Treatment with the IMP should be discontinued, and the withdrawal examination 
specified in Section 3.7.1.6 should be performed, in the cases listed below. Each 
investigator or subinvestigator will comprehensively review the circumstances and record 
the date and reason of discontinuation in a source document and a CRF. 
1) Legal representative or subject requests to be withdrawn 
2) After start of IMP administration, a deviation from the inclusion or exclusion 
criteria is discovered for the subject 
3) Continuation of treatment is deemed unfeasible due to the occurrence of AEs 
4) Any of the prohibited concomitant medications are used 
5) The dose and regimen of restricted concomitant medication were changed within 
24 hours before and after start of IMP administration 

 
 
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6) Excessive aquaresis is observed, or dose reduction to ≥2 dose steps lower is 
required due to concerns regarding the safety of the subject 
7) Liver function test value (AST or ALT) increased by ≥3 times the upper limit of 
the reference range for the subject’s age and gender 
8) Serum or blood sodium concentration increased by ≥12 mEq/L from that 
immediately before IMP administration, within 24 hours after administration 
9) Serum or blood sodium concentration increased by ≥8 mEq/L from that 
immediately before IMP administration, within 8 to 12 hours after administration 
10) Serum or blood sodium concentration exceeding 145 mEq/L is observed during 
the treatment period 
11) Serum or blood potassium concentration exceeds the upper limit of the reference 
range for the subject’s age and gender during the treatment period 
12) Subject’s pregnancy is confirmed or suspected 
13) The investigator or subinvestigator judges that withdrawal is necessary for any 
other reasons 
After start of treatment with the IMP, 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, when medically necessary due to AEs, when requiring treatment 
with a disallowed medication or therapy, or other issues, as determined by the 
investigator. However, options for continued treatment should be offered to the legal 
representative or subject 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 the IMP for a number of reasons including those listed below. 
 Reasons related to AEs: 
 Legal representative or subject decides to discontinue because of annoyance or 
discomfort due to a nonserious AE which is not otherwise determined to be an 
undue hazard 
 Continuing treatment with the IMP places the subject at undue risk as determined 
by the investigator or subinvestigator 
 Serious adverse event (SAE) 
 Other safety concerns or AEs that may possibly be related to the IMP 
 Death 
 Lost to follow-up 
 Poor IMP compliance 
 Pregnancy (see Section 5.5) 
 Major protocol deviations 
 Withdrawal of informed consent (complete written consent to withdrawal form) 

 
 
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 Termination of all or part of the trial by the sponsor 
 Other reasons unrelated to medical condition 
(including the case where the subject was found to deviate from any of the inclusion 
criteria or to meet any of the exclusion criteria, after start of IMP administration) 
 
If treatment is discontinued due to an AE, the investigator or subinvestigator will follow 
up the event according to Section 5.7. 
3.8.3.3 
Withdrawal of Consent 
All legal representatives and subjects have the right to withdraw their consent from 
further participation in the trial at any time without prejudice. Legal representatives and 
subjects cannot withdraw consent for use of data already collected as part of the trial, but 
only for future participation. The investigator or subinvestigator can also discontinue a 
subject’s participation in the trial at any time if medically necessary. Unless the legal 
representative provides his/her written withdrawal of consent or there is other written 
documentation by the investigator confirming the legal representative’s verbal intent to 
completely withdraw from the trial, the subject should be followed for all protocol-
specified evaluations and assessments, if possible. 
Complete withdrawal of consent requires the regal representative’s or subject’s refusal of 
ALL of the following procedures of follow-up (these procedures of follow-up will also be 
noted in the trial ICF). 
 Participation in all follow-up procedures specified in the protocol (whether in-site, by 
telephone, or by an in-home visit) 
 Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by legal representative and trial personnel) 
 Contact of the legal representative and 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, 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 legal representative’s intended withdrawal need to be completely 

 
 
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understood, documented, and managed to protect the rights of the subject and the 
integrity of the trial. A legal representative may initially express their desire to 
discontinue IMP administration, which is not equivalent to a complete withdrawal of 
consent for further participation (see Section 3.8.3.1). A legal representative 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 3.8.3.2 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 legal representatives who withdraw their 
permission for all of the above degrees of follow-up are considered to have completely 
withdrawn their consent for subject’s participation in the trial. 
3.8.3.4 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, the investigator or 
subinvestigator will meet/phone and discuss with the legal representative about 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, a legal representative signs an ICF), but who is not started on 
treatment. 
A subject for whom a legal representative signs an ICF, but who is not started on 
treatment is permitted to be re-screened as specified in Section 3.4.3. 
For a subject who meets the definition of screen failure, the following items will be 
recorded in a CRF for screen failure. 
 Date of investigation 
 Date on which the subject was determined to be a screen failure 
 Date of informed consent 
 Birth date 
 Gender 
 Race 
 Compliance with the inclusion criteria (Record the criterion number the subject did 
not meet, if any) 

 
 
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 Deviation from the exclusion criteria (Record the criterion number the subject met, if 
any) 
 Reason for screen failure 
 
3.10 
Definition of Completed Subjects 
Subjects who have received IMP administration at evaluation dose (see Section 7.4) for 3 
days will be defined as trial completers. 
3.11 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before the day of last observation, who do not 
have a known reason for discontinuation (eg, withdrew consent or AE), and for whom a 
survival status on the end of trial date 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, direct contact with the subject, 
medical records, successful telephone contact with the subject, statement by a family 
member or primary care physician, or public records). 
The investigator, subinvestigator, or designee will make 3 documented attempts to 
contact the subject by telephone, and in the event he/she is unable to reach the subject by 
telephone, he/she 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 record the following items for the subject lost to 
follow-up in a source document and a CRF. 
 Date of investigation 
 Investigation method 
 Contact with the subject (successful/unsuccessful) 
 Reason why the subject does not (cannot) visit 
 Presence or absence of AEs. If present, specify its name, dates of onset and resolution, 
severity, and IMP causality. 
 Action taken with the IMP, treatment for the event, and outcome 
 If the investigation is impossible, specify the reason 
 

 
 
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3.12 
Legal Representative or Subject Compliance 
During the trial period, a subject will be placed under the management of the investigator 
or subinvestigator. The investigator or subinvestigator will instruct a legal representative 
and subject to adhere to the following. 
 The IMP should be taken according to the specified dose and regimen 
 The specified schedule should be followed during the trial period 
 Prohibited concomitant medications (see Section 4.1) should not be used 
 The dose and regimen of restricted concomitant medications (see Section 4.2) should 
not be changed 
 Information obtained as a result of participation in the trial should not be divulged to 
a third party 
 
3.13 
Protocol Deviations 
The investigator or subinvestigator must not make deviations from or changes to the 
protocol without prior written agreement with the sponsor, as well as prior review and 
written approval by the IRB. 
The investigator or subinvestigator may make deviations from or changes to the protocol 
without prior written agreement with the sponsor or prior review and written approval by 
the IRB, if the deviations or changes cannot be avoided to eliminate immediate hazards to 
subjects or for other medical reasons. In such cases, the investigator should promptly 
submit a document stating the details and reason of deviation or change to the sponsor 
and the head of the trial site, and obtain approval from the IRB. In addition, the 
investigator should obtain approval from the head of the trial site and a written agreement 
from the sponsor through the head of the 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, 
subinvestigator, or designee will contact the sponsor at the earliest possible time by 
telephone. The investigator or subinvestigator and the 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. 

 
 
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2) Recording deviations 
The investigator or subinvestigator will record all deviations from the protocol in a 
source document. 
In addition, the investigator or subinvestigator will record certain specified items of 
the protocol deviations in a CRF according to the procedures for preparing a CRF 
provided by the sponsor. 
 
4 
Restrictions 
4.1 
Prohibited Concomitant Medications 
If any medication other than the IMP was used from the date of informed consent to the 
end of trial date, its name, indication, regimen, daily dose, administration route, and start 
and end dates should be recorded in a source document and a CRF. For therapy other 
than medication, its name, indication, and start and end dates should be recorded in a 
source document and a CRF. 
Concomitant use of medications and other substances listed in Table 4.1-1 and 
Table 4.1-2 is prohibited from the pretreatment observation period (3-1 days before start 
of tolvaptan administration) through the completion of an examination 2 days after final 
administration. This shall not apply to inevitable cases such as treatment for AEs. 
Table 4.1-1 
List of Medications Prohibited Before the Trial 
 
Drugs and foods that may be a strong inhibitors or inducers of CYP3A4 (see Table 4.1-2) 
 
Tolvaptan-containing drug products other than the IMP, mozavaptan hydrochloride 
 
Drugs unapproved in Japan 
 
Table 4.1-2 
Drugs and Foods That May Be a Strong Inhibitors or Inducers 
of CYP3A4 
Drug class 
Drug 
1) CYP3A4 inhibitors (excluding external agents) 
 
Antimicrobials 
Clarithromycin, erythromycin, fluconazole, 
itraconazole, miconazole, norfloxacin, 
chloramphenicol, voriconazole, telithromycin, 
ciprofloxacin, fosfluconazole, clotrimazole 
Calcium antagonists 
Diltiazem, verapamil 
Therapeutic drugs for gastritis/peptic ulcer 
Cimetidine 
Immunosuppressants 
Cyclosporine 
Anticancer drugs 
Imatinib, crizotinib 

 
 
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Table 4.1-2 
Drugs and Foods That May Be a Strong Inhibitors or Inducers 
of CYP3A4 
Anti-HIV drugs 
Indinavir, nelfinavir, ritonavir, saquinavir, 
delavirdine, atazanavir, fosamprenavir, lopinavir, 
darunavir, telaprevir, cobicistat 
Autonomic drugs 
Tofisopam 
Adenosine A2A receptor antagonists 
Istradefylline 
Antimetics 
Aprepitant 
Selective serotonin reuptake inhibitors 
Fluvoxamine 
2) CYP3A4 inducers (excluding external agents) 
 
Barbiturates 
Phenobarbital, amobarbital, pentobarbital, barbital, 
secobarbital 
Antiepileptics 
Carbamazepine, phenytoin 
Antitubercular drugs 
Rifampicin, rifabutin 
Psychostimulants 
Modafinil 
Anti-HIV drugs 
Efavirenz, nevirapine, etravirine 
Endothelin receptor antagonists 
Bosentan 
Anticancer drugs 
Enzalutamide 
Corticosteroid synthesis inhibitors 
Mitotane 
3) Foods containing substances that inhibit CYP3A4 
Grapefruit, Seville orange, star fruit, and their 
processed products 
4) Foods containing substances that induce 
CYP3A4 
Foods containing St. John’s wort 
HIV = human immunodeficiency virus 
 
4.2 
Restricted Concomitant Medications 
The dose and regimen of the following medications should not be changed from the 
pretreatment observation period through the completion of an examination 2 days after 
final administration in principle. Change of dose and regimen during this period is 
allowed if it is required for safety reasons. In such cases, “the reason of change” and “the 
details of change” should be recorded. Within 24 hours before and after first tolvaptan 
administration, however, the dose and regimen of restricted concomitant medications 
should not be changed (if changed, the subject’s participation in the trial should be 
discontinued). 
 Therapeutic drugs for heart failure (injectables): Catecholamine preparations, human 
atrial natriuretic peptide preparations, phosphodiesterase 3 inhibitors, colforsin 
preparations, etc 
 Diuretics (oral preparations and injectables) 
 

 
 
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5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as medical history at screening for preplanned 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 hospitalization should be reported. 
 Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs. 
 Congenital anomaly/birth defect. 
 Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or 
convulsions that do not result in hospitalization, or the development of drug 
dependency or drug abuse. 
 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 

 
 
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Immediately Reportable Event (IRE): 
 Any SAE 
 Any AE related to occupational exposure 
 Potential drug induced liver injury (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 in the “Adverse event” section of a 
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 the 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 in a 
CRF. The intensity of an AE is defined as follows: 
1 = Mild:  
Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: 
Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: 
Inability to work or perform normal daily activity. 
 
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE. 
Not Related:  
There is no temporal or causal relationship between the IMP and 
the AE. 
 

 
 
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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 from informed consent to the end of trial must be recorded in source 
documents and CRFs provided by the sponsor. 
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition. If an AE that 
has been previously reported worsens and its severity or seriousness changes, it should be 
reported as a new AE in a CRF. 
In addition, the sponsor must be notified immediately by e-mail of any IRE which 
occurred from the time of informed consent by a legal representative to the end of trial, 
according to the procedure outlined in Section 5.3. Special attention should be paid to 
recording hospitalization and concomitant medications. 
In a CRF, the following items should be recorded according to the procedures for 
preparing a CRF provided by the sponsor. 
 Event name 
 Date of onset (also time of onset, if possible, during hospitalization) and date of 
resolution 
 Severity 
 Seriousness (if serious, specify the details) 
 IMP causality 
 Action taken with the IMP 
 Outcome 
 
5.3 
Immediately Reportable Events 
The investigator or subinvestigator must immediately report after either the investigator, 
subinvestigator, or designee becomes aware of any IRE, by e-mail to the sponsor using 
the contact information on the cover page of this protocol. 

 
 
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An IRE form must be completed and sent by e-mail to the sponsor. Please note that the 
IRE form is NOT the “Adverse event” section of the CRF. Due regard should be paid to 
privacies when sending the IRE form or other documents by e-mail, etc. 
Subjects experiencing SAEs should be followed until the events are resolved, stabilized, 
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 AST or ALT that is ≥3 times the upper 
limit of the reference range for their age and gender, a total bilirubin level should also be 
evaluated. If the total bilirubin is ≥2 times the upper limit of the reference range for their 
age and gender, the investigator or subinvestigator should record all these values in an 
IRE form and promptly report to the sponsor according to the procedure specified in 
Section 5.3 Immediately Reportable Events. 
5.5 
Pregnancy 
Before enrolling a female who has begun menstruation in this trial, the investigator or 
subinvestigator must review the guidelines about trial participation with all female 
subjects who have begun menstruation. The topics should generally include: 
 Informed consent form 
 Guidelines for the follow-up of a reported pregnancy 
Before trial enrollment, the legal representative of the female subject (potential female 
subject) who has begun menstruation must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The legal representative must sign an informed consent form stating that the 
above-mentioned risk factors and consequences were discussed with her. 
A urine pregnancy test for human chorionic gonadotropin (hCG) will be performed at 
screening on all females who have begun menstruation. If a urine test is performed and is 
positive, the investigator or subinvestigator will follow up with a confirmatory serum test. 

 
 
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During the trial period, all female subjects and legal representatives should be instructed 
to contact the investigator or subinvestigator immediately if they suspect they might be 
pregnant. 
If a subject is suspected to be pregnant before she receives the 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 the IMP, the 
IMP must be withheld immediately (if reasonable, taking into consideration any potential 
withdrawal risk) until the result of serum pregnancy test is known. If pregnancy is 
confirmed, the IMP will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for the subject’s 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 period and for 30 days after 
final IMP administration, and record the event on an 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). Other appropriate 
pregnancy follow-up procedures should be considered, if indicated. In addition, the 
investigator or subinvestigator must report to the sponsor, on appropriate Pregnancy 
Surveillance Form(s), follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome. Infants will be followed for a minimum of 6 
months from the date of birth. 
5.6 
Procedure for Breaking the Blind 
Not applicable 
5.7 
Follow-up of Adverse Events 
For this trial, information on AEs will be collected until the follow-up examination 
performed 5-7 days after final IMP administration (hereinafter referred to as “the end of 
trial date”). 
After the end of trial date, an AE falling into any of categories in Section 5.7.1, 
Section 5.7.2, and Section 5.7.3 will be followed as specified. 

 
 
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5.7.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial period must be recorded on 
the “Adverse event” section of the CRF with the current status noted. If a subject has an 
AE or has not recovered from an AE at the end of trial date, follow-up contacts will be 
scheduled at least every 4 weeks until the event is resolved, stabilized, or the subject is 
lost to follow-up. All nonserious AEs that are ongoing at the end of trial date will be 
recorded as ongoing in a 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 end of trial 
date will be recorded in the subject’s medical record. 
5.7.2 
Follow-up of Serious Adverse Events 
This trial requires that subjects be actively monitored for SAEs up to the end of trial date. 
If a subject has an AE or has not recovered from an AE at the end of trial date, follow-up 
contacts will be scheduled at least every 4 weeks until the event is resolved, stabilized, or 
the subject is lost to follow-up. 
Serious AEs that are identified or ongoing at the end of trial date must be recorded on the 
“Adverse event” section of the CRF and reported to the sponsor according to the 
reporting procedure outlined in Section 5.3. All SAEs that are ongoing at the end of trial 
date will be recorded as ongoing in a CRF. This may include unresolved previously 
reported SAEs, or new SAEs. The investigator or subinvestigator will follow SAEs until 
the events are resolved, stabilized, or the subject is lost to follow-up. The investigator or 
subinvestigator will continue to report any significant follow-up information to the 
sponsor until the event is resolved or stabilized, or the subject is lost to follow-up with 
and IRE form. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring 
After End of Trial Date (Last Scheduled Contact) 
Any new SAE reported by the subject to the investigator or subinvestigator that occur 
after the end of trial date, and are determined by the investigator or subinvestigator to be 
related to the IMP, should be reported to the sponsor. The investigator or subinvestigator 
should follow SAEs identified after the end of trial date 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 or stabilized, or the subject is lost to follow-up with and IRE form. 

 
 
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6 
Pharmacokinetic/Pharmacodynamic Analysis 
6.1 
Pharmacokinetic Analysis 
In the pharmacokinetic analysis set (see Section 7.2), the plasma concentrations of 
OPC-41061 and its metabolites (DM-4103 and DM-4107) will be summarized by 
descriptive statistics, in the following 2 ways. 
 Summarization for each compound, time point of blood sampling, and dose per unit 
of body weight 
 Summarization for each compound, time point of blood sampling, dose per unit of 
body weight, and age group (young age, 6 months to less than 2 years; middle age, 2 
years to less than 7 years; and old age, 7 years to less than 15 years) 
 
Descriptive statistics to be determined are the number of subjects, mean, standard 
deviation, coefficient of variation, minimum, median, and maximum. 
The population pharmacokinetic analysis of OPC-41061 will be separately performed and 
reported. 
6.2 
Pharmacodynamic Analysis 
A pharmacodynamic analysis will be performed in the pharmacodynamic analysis set 
(see Section 7.2). For the items listed below, descriptive statistics (the number of subjects, 
mean, standard deviation, minimum, median, and maximum) of measured values and 
changes from baseline (immediately before tolvaptan administration) at each time point 
after start of administration at evaluation dose (see Section 7.4) will be determined. 
As a subgroup analysis, the items will also be analyzed for each age group (young age, 6 
months to less than 2 years; middle age, 2 years to less than 7 years; and old age, 7 years 
to less than 15 years). 
The same analysis will be performed for each evaluation dose (0.05, 0.15, 0.3, and 
0.5 mg/kg/day) (in the entire and each age group). 
In the subgroup analysis and the analysis by evaluation dose, data collected on the day 
after the third day of administration at evaluation dose, the day after final administration 
at evaluation dose, and the day after final administration will be analyzed. 

 
 
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An analysis will also be performed using data collected immediately before start of 
administration at evaluation dose as a baseline. In addition, data will be summarized by 
the number of days elapsed since start of administration. 
 Daily fluid intake 
 Daily fluid balance 
 Serum osmolality 
 Serum or blood sodium concentration 
 Serum or blood potassium concentration 
 Urine osmolality 
 Daily urine sodium excretion 
 Daily urine potassium excretion 
 Plasma AVP concentration 
 
7 
Statistical Analysis 
7.1 
Sample Size 
For the primary endpoint, the required sample size was set by first setting the threshold 
value for assessment of efficacy, and then using binomial distribution to determine the 
number of subjects required to maintain a 90% or higher probability that the lower limit 
of the 95% CI for the percentage of subjects achieving the primary endpoint will be 
above the threshold value. 
As reference information for the threshold value and binomial distribution parameter 
required to set the sample size for the trial, a threshold of 0.3 and a binomial distribution 
parameter of 0.5 to 0.6 were used based on interviews with clinicians, since no clinical 
trial results for administration of tolvaptan in pediatric patients have been obtained either 
in Japan or other countries. 
Based on the above, the required number of subjects was calculated to be a minimum of 
68 for a parameter of 0.5 and a minimum of 30 for a parameter of 0.6. 
A sample size of 30 to 68 subjects was therefore considered to be appropriate, and in 
view of feasibility the number of subjects for the trial was set at 60. 
 

 
 
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7.2 
Datasets for Analysis 
The full analysis set (FAS) includes all subjects who received at least 1 dose of the IMP 
and have postdose data on body weight and daily urine volume. 
The dose maintenance analysis set includes all subjects who received administration at 
same dose for at least 3 days in the full dataset. 
The safety analysis set (SAS) includes all subjects who received at least 1 dose of the 
IMP. 
The pharmacokinetic analysis set includes all subjects who received at least 1 dose of the 
IMP and have postdose data on drug concentration. 
The pharmacodynamic analysis set includes all subjects who received at least 1 dose of 
the IMP and have postdose pharmacodynamic data. 
7.3 
Handling of Missing Data 
If data on body weight and edematous symptoms cannot be obtained at assessment on the 
day after the third day of administration at evaluation dose, the missing data will be 
imputed using the last available data obtained by that day. If data on body weight on the 
day after the third day of administration at evaluation dose cannot be obtained, the 
definition of primary endpoint, “the mean daily urine volume for the 3 days of treatment 
at evaluation dose” (Section 3.5.1), will be changed to “the mean daily urine volume 
from start of administration at evaluation dose to the day on which the imputed data on 
body weight is obtained”. 
7.4 
Definition of Evaluation Dose 
Of the doses administered as specified in Section 3.2.2 and Section 3.2.3, the dose 
meeting the following criteria is defined as an evaluation dose. 
1) If sufficient increase in urine volume was obtained during the course of dose 
escalation, or if the dose was increased to 0.5 mg/kg/day because sufficient 
increase in urine volume was not obtained: 
 If the dose was not subsequently reduced, then that dose 
 If the dose was reduced without having been administered for 3 days, then the 
reduced dose 
 If the dose was reduced after having been administered for 3 days, then the 
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2) If IMP administration was discontinued before sufficient increase in urine volume 
was obtained during the course of dose increase: 
 The dose at final IMP administration 
 
Other definitions of evaluation dose will be considered if necessary. 
 
7.5 
Primary and Secondary Endpoint Analyses 
The following analyses will be performed in the full analysis set. As a subgroup analysis, 
the items will also be analyzed for each age group (young age, 6 months to less than 2 
years; middle age, 2 years to less than 7 years; and old age, 7 years to less than 15 years). 
The same analysis will be performed for each evaluation dose (0.05, 0.15, 0.3, and 
0.5 mg/kg/day) (in the entire and each age group). 
In the subgroup analysis and the analysis by evaluation dose, data collected on the day 
after the third day of administration at evaluation dose, the day after final administration 
at evaluation dose, and the day after final administration will be analyzed. 
The same analysis will be performed in the dose maintenance analysis set. 
Efficacy will be comprehensively assessed based on the results of primary and other 
endpoints. 
7.5.1 
Primary Endpoint Analysis 
The definition of primary endpoint is presented in Section 3.5.1. 
The number and percentage of subjects as well as exact 95% CI based on binomial 
distribution will be calculated. The same calculations will be performed regarding body 
weight on the day after final administration at evaluation dose and the day after final 
administration. The number and percentage of subjects will also be calculated for each 
time point after the start of administration at evaluation dose. 
An analysis will also be performed using data collected on the first day of administration 
at evaluation dose as a baseline. 
7.5.2 
Secondary Endpoint Analysis 
7.5.2.1 
Percent Change in Body Weight 
For body weight measured on the day after the third day of administration at evaluation 
dose, the day after final administration at evaluation dose, and the day after final 

 
 
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administration, and their percent changes from baseline (before start of tolvaptan 
administration on the first day of the treatment period), the number of subjects, mean, 
standard deviation, minimum, median, maximum, and 95% CI will be calculated. The 
descriptive statistics will also be calculated for each time point after start of 
administration at evaluation dose. 
An analysis will also be performed using data collected on the first day of administration 
at evaluation dose as a baseline. In addition, data will be summarized by the number of 
days elapsed since start of administration. 
7.5.2.2 
Edematous Symptoms (Edema [Lower Limbs, Eyelids, etc], 
Dyspnea, Jugular Venous Distension, Pulmonary Congestion, 
Cardiothoracic Ratio, Respiration Rate at Rest, Pulse Rate, and 
Pleural Effusion), Central Venous Pressure (Only Subjects With 
Central Venous Catheterization), and Retention of Pericardial 
Effusion (Only Subjects Requiring Echocardiography) 
7.5.2.2.1 
Edema (Lower Limbs, etc) and Pulmonary Congestion 
A shift table will be prepared for changes in the degree of each symptom from baseline 
(the pretreatment observation period) to the day after third day of administration at 
evaluation dose, the day after final administration at evaluation dose, and the day after 
final administration. In addition, the percentages of subjects who show remarkable 
improvement or improvement, and the percentages of subjects whose symptoms observed 
before tolvaptan administration is resolved after administration on the day after third day 
of administration at evaluation dose, the day after final administration at evaluation dose, 
and the day after final administration will be determined. 
An analysis will also be performed using data collected immediately before start of 
administration at evaluation dose as a baseline. In addition, data will be summarized by 
the number of days elapsed since start of administration. 
 
Table 7.5.2.2.1-1 
Degree of Improvement for Edema and Pulmonary Congestion 
 
Degree of improvement 
Criterion 
1 
Remarkable improvement 
Symptom resolution or improvement to at least 2 grades better 
2 
Improvement 
Symptom improvement to 1 grade better (symptom resolution should 
be assessed as remarkable improvement) 
3 
No change 
No change in the degree of symptom, or no symptom observed 
throughout the trial period 
4 
Worsening 
Symptom worsening to at least 1 grade worse 
 

 
 
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7.5.2.2.2 
Edema (Eyelids), Jugular Venous Distension, Dyspnea, and 
Pleural Effusion 
A shift table will be prepared for changes in the degree of each symptom from baseline 
(the pretreatment observation period) to the day after third day of administration at 
evaluation dose, the day after final administration at evaluation dose, and the day after 
final administration. In addition, the percentages of subjects whose symptoms observed 
before tolvaptan administration is resolved after administration on the day after third day 
of administration at evaluation dose, the day after final administration at evaluation dose, 
and the day after final administration will be determined. 
An analysis will also be performed using data collected immediately before start of 
administration at evaluation dose as a baseline. In addition, data will be summarized by 
the number of days elapsed since start of administration. 
7.5.2.2.3 
Cardiothoracic Ratio, Respiration Rate at Rest, and Pulse 
Rate 
Descriptive statistics of measured values and changes from baseline (the pretreatment 
observation period) on the day after third day of administration at evaluation dose, the 
day after final administration at evaluation dose, and the day after final administration 
will be calculated. The same calculations will be performed for each time point after start 
of administration at evaluation dose. 
An analysis will also be performed using data collected immediately before start of 
administration at evaluation dose as a baseline. In addition, data will be summarized by 
the number of days elapsed since start of administration. 
7.5.2.2.4 
Central Venous Pressure 
Descriptive statistics of postdose measured values and changes from baseline (the 
pretreatment observation period) will be calculated. 
7.5.2.2.5 
Retention of Pericardial Effusion 
The frequency distribution of postdose measured values (decrease, no change, or 
increase) will be determined. 
7.5.2.3 
Daily Urine Volume 
Descriptive statistics of measured values and changes from baseline (the pretreatment 
observation period) will be calculated for each time point after start of administration at 
evaluation dose. 

 
 
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An analysis will also be performed using data collected immediately before start of 
administration at evaluation dose as a baseline. In addition, data will be summarized by 
the number of days elapsed since start of administration. 
7.6 
Analysis of Demographic and Baseline Characteristics 
In the safety analysis set, frequency distributions or descriptive statistics of the following 
subject characteristics will be determined. 
 Age 
 Gender 
 Height 
 Race 
 Presence/absence of complication 
 Presence/absence of medical history 
 Etiology of heart failure 
 
7.7 
Safety Analysis 
7.7.1 
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities preferred term. The incidence of the following events will be summarized. 
 Treatment-emergent AEs (TEAEs) 
 TEAEs by severity 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP. 
The above AEs will also be summarized by evaluation dose. In addition, summaries by 
evaluation dose after start of administration at evaluation dose and by age group will be 
prepared.  
7.7.2 
Clinical Laboratory Data 
For clinical laboratory tests other than qualitative urinalysis, descriptive statistics of 
measured values and changes from baseline (immediately before tolvaptan 
administration) at each time point after start of administration at evaluation dose and at 

 
 
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final administration will be calculated. For qualitative urinalysis parameter, shift tables at 
each time point after start of administration at evaluation dose and at final administration 
compared with baseline will be prepared. For clinical laboratory test parameters other 
than qualitative urinalysis, a specified reference range will be used to classify 
measurements into measurement “within the reference range”, “below the reference 
range”, or “above the reference range”, and shift tables of classifications at each time 
point after start of administration at evaluation dose and at final administration compared 
with baseline will be prepared. 
An analysis will also be performed using data collected immediately before start of 
administration at evaluation dose as a baseline. In addition, data will be summarized by 
the number of days elapsed since start of administration. 
7.7.3 
Vital Signs Data 
For vital signs, descriptive statistics of measured values and changes from baseline (the 
pretreatment observation period) at each time point after start of administration at 
evaluation dose and at final administration will be calculated. 
An analysis will also be performed using data collected immediately before start of 
administration at evaluation dose as a baseline. In addition, data will be summarized by 
the number of days elapsed since start of administration. 
7.7.4 
12-lead Electrocardiogram Data 
For each 12-lead ECG parameters, descriptive statistics of measured values and changes 
from baseline (the pretreatment observation period) will be calculated at each time point 
after start of administration at evaluation dose and at final administration. 
For QTc interval, the number and percentage of subjects with a QTc interval of >450, 
>480, or >500 ms at any time point from baseline through the day after final 
administration will be calculated. The number and percentage of subjects with a change 
in QTc interval from baseline of >30 or >60 ms at any time point from start of treatment 
through the day after final administration will also be calculated. A shift table for QTc 
interpretation (normal or abnormal) will be prepared from baseline through the day after 
final administration. 
In addition, data will be summarized by the number of days elapsed since start of 
administration. 
 

 
 
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8 
Management of Investigational Medicinal Product 
For full details on IMP management, refer to the IB and clinical operation manual. 
8.1 
Packaging and Labeling 
The IMP will be provided to an IMP manager by the sponsor or a designated agent. The 
IMP will be supplied in bottles and packages. Each bottle and package for the IMP used 
in the treatment period will be labeled clearly stating “For trial use only”, protocol 
number, IMP name, quantity, lot number, expiration date, storage conditions, and 
sponsor’s name and address. 
8.2 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP manager. The IMP manager should not provide the IMP to any subject not 
participating in this protocol. The IMP will be stored at room temperature. A trial site 
staff will measure and record a temperature in the IMP storage area at least once each 
work day and maintain a temperature log. 
8.3 
Accountability 
The IMP manager must maintain an inventory record of IMP (investigational drug, active 
control drug, or placebo) 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 and trial site number on an outermost shipping 
container. Returned supplies should be in their original containers. 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 the identity, quality, labeling, packaging, 
reliability, safety, durability, tampering, counterfeiting, theft, effectiveness or 

 
 
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performance of a drug product or medical device after it is released for distribution. 
Examples include, but are not limited to, communications involving: 
 Failure/malfunction of a product to meet any of its specifications 
 Incorrect or missing labeling 
 Packaging issues (eg, damaged, dirty, crushed, missing product) 
 Blister defects (eg, missing, empty blister) 
 Bottle defects (eg, under/over-fill, no safety seal) 
 Vial defects 
 Product defect (eg, odor, chipped, broken, embossing illegible) 
 Loss or theft of product 
 
8.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator, subinvestigator or designee must record all PQCs identified through any 
mean during the period from the receipt of the IMP from the sponsor, or sponsor’s 
designee, through and including reconciliation and up to destruction, including subject 
dosing. The investigator, subinvestigator, or designee must provide the sponsor (or 
sponsor’s designee) with information listed in Section 8.5.2 (Information Required for 
Reporting Product Quality Complaints) by e-mail (destination address: PQC_156-102-
00123@otsuka.jp) immediately after becoming aware of a PQC. 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow the reporting mechanisms listed above. 
8.5.2 
Information Required for Reporting Product Quality Complaints 
 Description of compliant 
 Reporter identification (eg, subject, investigator/subinvestigator, trial site) 
 Reporter contact information (eg, address, phone number, e-mail address) 
 ID of material (product/compound name, Kit number or bottle number) 
 Clinical protocol reference (number and/or trial name) 
 Dosage form/strength (if known) 
 Pictures (if available) 
 Complaint sample availability for return 
 

 
 
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8.5.3 
Return Process for Product Quality Complaints 
At the time of reporting a PQC, the availability of complaint sample for return should be 
notified. If complaint sample is available for return, the sponsor will provide instructions 
for sample return, when applicable. 
It must be documented in a site accountability record that the complaint sample 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 include but are not limited to medical records, 
electronic data, screening logs, and recorded data from automated instruments. Source 
documents for measurements of plasma drug concentration will be retained by the 
bioanalytical laboratory. The sponsor will retain an electronic file submitted by the 
bioanalytical laboratory as a copy. 
All source documents pertaining to this trial will be maintained by the trial site and made 
available for direct inspection by authorized persons. The investigator or trial site will 
permit trial-related monitoring, audit, IRB review, and regulatory inspection by providing 
direct access to source data/documents. Persons with direct access will be presented in an 
ICF. In all cases, subject privacy must be maintained in accordance with local regulatory 
requirements. 
9.2 
Data Collection 
During each subject’s visit to the trial site, the investigator or subinvestigator will keep a 
medical record to document all significant observations. At a minimum, the medical 
record should contain:  
 Documentation of informed consent process, including any revised consent 
 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, 
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 Date of the visit and the corresponding Visit or Day in the trial schedule 
 Subject’s general status remarks, including any significant medical finding. The 
severity, frequency, duration, action taken, and outcome of any AE, and the 
investigator’s or subinvestigator’s assessment of relationship to the IMP must also be 
recorded. 
 Any change in concomitant medications or their doses 
 General reference to procedures completed 
 Signature (or initials) and date of the investigator or subinvetigator (or designee) who 
made an entry in the medical record (if an electronic data system is used, a full audit 
trail must be maintained) 
 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the medical record as 
described above. Any change to information in the medical record and other source 
documents will be initialed and dated on the day the change is made by a trial site staff 
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 document by the investigator or 
subinvestigator. If an electronic data system is used, a full audit trail of changes must be 
maintained. 
Information from the medical record and other source documents will be entered by a 
trial site staff directly into electronic CRFs in the sponsor’s electronic data capture (EDC) 
system. Changes to the data will be captured by an automatic audit trail. 
Data on plasma drug concentration measured by the bioanalytical laboratory and ECG 
measurement result obtained by the central ECG reading facility will be directly 
transferred from each facility to the sponsor or the Clinical Research Organization. Data 
the sponsor will collect include: 
 Case report form (data collected after informed consent) 
 12-lead ECG measurement report 
 Table of drug concentration measurements (copy) 
 Measurements of laboratory tests, urine osmolality, plasma AVP concentration, etc 
 
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 and as required by applicable local regulations. 

 
 
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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, whichever is longer. However, if the sponsor requires a longer period of 
archiving, the trial site will consult with the sponsor on the period and procedure of 
record retention. 
 Period until 2 years after manufacturing and marketing approval date. However, if the 
trial site receives notification from the sponsor that development has been terminated 
or that the results of the trial will not be submitted with an approval application, 
period until 3 years after receipt of such notification. 
 Period until 3 years after termination or completion of the trial 
 
The trial site must not dispose of any record relevant to this trial without either (1) written 
permission from the sponsor or (2) provision of an opportunity for the sponsor to collect 
such record. 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 a data clarification form received from the sponsor. Such documents 
are 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 local 
regulatory requirements. As part of a concerted effort to fulfill these obligations 
(maintain current personal knowledge of the progress of the trial), the sponsor’s monitors 
will visit the trial site during the trial, as well as communicate periodically via telephone, 
e-mail, and written communications. In addition, all investigators or subinvestigators and 
trial site staff 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. 
Audit items include, but are not limited to, IMP supply, the presence of required 

 
 
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documents, informed consent process, and comparison of data in CRFs with those in 
source documents. The investigator agrees to participate with audits. 
Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs. 
 
11 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Sciences guidelines, and applicable local laws and 
regulations. Each trial site will seek approval/favorable opinion by an IRB according to 
local requirements, and provide that documentation to the sponsor. The IRB will evaluate 
the ethical, scientific and medical appropriateness of the trial. In preparing and handling 
documents such as a CRF and IRE form, the investigator or subinvestigator and his/her 
staff will take measures to ensure adequate care in protecting subject privacy. To this end, 
a subject number and subject identifier will be used to identify each subject. Financial 
aspects, subject insurance, and the publication policy for the trial will be documented in 
the agreement between the sponsor and the trial site. 
 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region where the trial is 
conducted should be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy trial-related 
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 regulatory 
authorities or other authorized officials if necessary, according to local regulations. 
 

 
 
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13 
Amendment Policy 
The investigator should not make any change 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 should wait for IRB approval/favorable opinion of the amended protocol 
before implementing the change(s). Administrative amendments are defined as changes 
that have no effect on the safety of subjects, the 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 
and notified to the IRB within a local applicable timelines. The sponsor will submit the 
protocol amendments to applicable regulatory agencies within a local applicable 
timelines. 
When the IRB, investigator, and/or sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to subjects, the 
currently approved ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IRB, informed consent will be obtained 
again from the legal representatives of enrolled subjects 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 the International Committee of Medical Journal Editors (ICMJE) 
authorship criteria (http://www.icmje.org/recommendations). According to ICMJE 
guidelines, one may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 

 
 
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All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 
 
15 
References 
1 
Japanese Society of Pediatric Cardiology and Cardiac Surgery. The Clinical 
Guideline for Medical Treatment of Pediatric Heart Failure (JSPCCS 2015) Japanese 
Society of Pediatric Cardiology and Cardiac Surgery 
2 
Higashi K, Murakami T, Ishikawa Y, Itoi T, Ohuchi H, Kodama Y, et al. Efficacy and 
safety of tolvaptan for pediatric patients with congestive heart failure. Multicenter 
survey in the working group of the Japanese Society of Pediatric Circulation and 
Hemodynamics (J-SPECH). Int J Cardiol. 2016;205:37-42. 
3 
Ministry of Health, Labour and Welfare. Handbook of Health and Welfare Statistics 
2016 
4 
International Conference on Harmonisation (ICH) [homepage on the Internet]. E6: 
Good Clinical Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 
Jun 10; cited 2015 May 29]. Available from: 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html. 
5 
The Guideline for Kidney Function Assessment to Diagnose Pediatric Chronic 
Kidney Disease (Pediatric CKD). Research Program for Overcoming Intractable 
Diseases; Health, Labour and Sciences Research Grants in FY2013; Group for the 
Elucidation of Natural History and the Establishment of Early Diagnosis and Therapy 
to Inhibit the Progression of Kidney Failure in Pediatric Chronic Kidney Diseases 
Including Congenital Anomalies of the Kidney and Urinary Tract (Pediatric CKD 
Study Group in Japan), ed. 
6 
Forrester JS, Diamond G, Chatterjee K, Swan HJC. Medical therapy of acute 
myocardial infarction by application of hemodynamic subsets (first of two parts). N 
Engl J Med. 1976;295(24):1356-62. 
 
 
 

 
 
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Appendix 1 
Handling and Shipment of Bioanalytical Samples 
1) Handling of pharmacokinetic blood samples 
All sample stock tubes will be labeled to provide necessary information including the 
protocol number, subject identifier, and time point of blood sampling. Approximately 
1 mL of blood will be collected in a blood-collecting tube containing heparin sodium 
(for blood sampling of 2 mL) through an indwelling catheter or direct venipuncture. 
The tube will slowly be turned upside down several times to mix the blood and put 
into ice water. The status (collected/not collected), and exact date and time of 
collecting a pharmacokinetic blood sample will be recorded in a CRF. Then, the 
blood will immediately (within 60 minutes after sampling) be centrifuged at 
approximately 1710 × g for approximately 10 minutes at approximately 4°C. 
Separated plasma will be taken into a sample stock tube. The plasma sample will be 
stored at −15°C or lower temperature. 
2) Shipment of bioanalytical samples 
The central laboratory will collect frozen samples with dry ice from trial sites and 
store them at −15°C or lower temperature. Then, the samples will be shipped with dry 
ice to the bioanalytical laboratory according to the shipment schedule decided after 
consultation with the sponsor. 
 
 
 

 
 
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Appendix 2 
Protocol Amendment(s)/Administrative Change(s) 
Amendment Number: 1 
Issue Date: 
31 Mar 2017 
PURPOSE: 
To correct entry omissions, clerical errors, etc 
 
BACKGROUND:  
Corrections were made because entry omissions, clerical errors, etc were found. 
 
MODIFICATIONS TO PROTOCOL: 
 Entire Protocol: “Serum potassium concentration” was changed to “serum or blood 
potassium concentration”. 
 Protocol Synopsis (Trial Duration): The durations for the treatment period and 
follow-up period were corrected. 
 Section 3.4.3 (Exclusion Criterion 15): 
“Breastfed patients” was changed to “Breastfed patients (excluding those patients 
whose fluid intake can be measured by expressed breast milk or other ways, and 
whose mother does not use any of prohibited/restricted concomitant medications from 
1 week before informed consent to completion of an examination 2 days after final 
administration)” (for clarification). 
 Section 3.7.1.16.1 Fourth Day of Administration at Dose Decided for Each Individual 
Subject: The following test items were added (due to entry omissions). 
Before tolvaptan administration: Plasma AVP concentration (only subjects from 
whom samples are available), plasma drug concentration (when blood sample for 
measurement of plasma drug concentration was collected on the previous day), daily 
urine volume, daily fluid intake, daily fluid balance, urine sodium excretion, urine 
potassium excretion, urine osmolality 
At a feasible time: 12-lead ECG, chest x-ray 
 Section 3.7.1.16.2 to Section 3.7.1.16.4 Fifth to Seventh Day of Administration at 
Dose Decided for Each Individual Subject: The following test items were added (due 
to entry omissions). 
Before tolvaptan administration: Daily urine volume, daily fluid intake, daily fluid 
balance, urine sodium excretion, urine potassium excretion, urine osmolality 
 Section 3.7.1.17.1 First Day of Administration at Reduced Dose: The following test 
items were added (due to entry omissions). 
At a feasible time: 12-lead ECG 
 Section 3.7.1.17.4 Fourth Day of Administration at Reduced Dose (the fourth day of 
administration at reduced dose and the day after): The following test items were 
added (due to entry omissions). 

 
 
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Before tolvaptan administration: Plasma AVP concentration (only subjects from 
whom samples are available), plasma drug concentration (when blood sample for 
measurement of plasma drug concentration was collected on the previous day) 
At a feasible time: 12-lead ECG, chest x-ray 
 Section 3.7.4.2.4 and Section 3.7.4.2.5: 
“In that case, however, the same measurement procedure should be followed for each 
subject.” was added. 
 Section 3.7.4.2.6: 1) Urine sample processing (screening period) was deleted (due to 
clerical error). 
 Section 3.11: “Treatment compliance” was deleted (due to clerical error). 
 Others: Scheduled assessment procedures were clarified. 
 
 
 

 
 
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Amendment Number:  2 
Issue Date:  
06 Jun 2017 
PURPOSE:  
To correct entry omissions, clerical errors, etc 
 
BACKGROUND:  
Corrections were made because entry omissions, clerical errors, etc were found. 
 
MODIFICATIONS TO PROTOCOL: 
 Entire Protocol: Sections to describe procedures when treatment at the dose decided 
for each individual subject is completed in 3 days, when treatment at the dose decided 
for each individual subject is extended, and on the day and 2 days after extended 
treatment at reduced dose were created (for clarification). 
 Section 3.7.1.2.3: Confirmation that a subject does not meet Exclusion Criterion 1 
was added (due to entry omission). 
 Section 3.7.1.7: 12-lead ECG was added (due to entry omission). 
 Section 3.7.2.4.1: Items to be recorded was changed from “the date and time of 
assessment” to “the date of assessment” (due to inconsistency with description in 
Section 3.7.2.4). 
 Section 7.3: It is described that the missing data on body weight and edematous 
symptoms will be imputed using the last available data when the data on the day after 
the third day of administration at evaluation dose cannot be obtained, without limiting 
the case to treatment discontinuation. Correspondingly, it is also described that the 
definition of primary endpoint (mean daily urine volume) will be changed to the 
mean of measurements collected until the day on which the imputed data is obtained 
(due to entry omissions regarding missing data for reasons other than treatment 
discontinuation). 
 Section 15 (Reference 3): The cited literature was changed (to more appropriate one). 
 Appendix 1, 1): The period from blood sampling to centrifugation was set longer (to 
increase the procedure feasibility). 
 Others: Scheduled assessment procedures were clarified. 
 
 

 
 
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Amendment Number:  3 
Issue Date:  
03 Feb 2021 
PURPOSE:  
To make corrections due to extended trial duration, collection of spot urine data in 
pharmacodynamic assessments, entry omissions, clerical errors, etc 
 
BACKGROUND:  
The trial duration was corrected because the period of subject enrollment is extended. 
Corrections were also made because entry omission (a note that data collected centrally 
does not have to be entered in the EDC system), clerical errors, etc were found. 
 
MODIFICATIONS TO PROTOCOL: 
 Protocol Synopsis (Trial Duration): The end date for the duration of the trial was 
changed from Jun 2021 to Nov 2021 (due to extended trial duration). 
 Section 3.7.1.3.10 “1) Before tolvaptan administration” Plasma drug concentration: 
was deleted (due to clerical error). 
 Section 3.7.3.2, Section 3.7.4.2.3, Section 3.7.4.2.4, Section 3.7.4.2.5, 
Section 3.7.4.2.6, Section 3.7.4.2.7, Section 3.7.4.2.8, Section 3.7.4.2.9: “The result 
of measurement by the specified central laboratory does not have to be recorded.” 
was added (due to entry omission).  
 Section 3.7.4.2.6, Section 3.7.4.2.7, Section 3.7.4.2.8 [1) Urine sample processing 
(pretreatment observation period and treatment period)]: It is additionally described 
that data on spot urine sample will be collected when an examination is conducted 
using spot urine, and some clerical errors were corrected. 
 Section 5.3, Section 11: Descriptions about an IRE form were added (Because an IRE 
form becomes available for reporting, in addition to a SAE form). 
 Section 9.2: “Measurements of laboratory tests, urine osmolality, plasma AVP 
concentration, etc” was added (due to entry omission). 
 
 
 

 
 
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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 medicinal product, tolvaptan (OPC-41061), the 
concomitant 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 trial site where tolvaptan (OPC-41061) 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 in case report forms by me, the 
subinvestigator, or 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 trial sites, whenever applicable. I agree to allow the sponsor, its designee monitors and 
auditors full access to all medical records at the trial site for subjects screened or enrolled in the 
trial. 
 
I agree to await IRB approval before implementation of any substantial amendment 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 timeline. 
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 experience 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 is digitally signed. The electronic signature is attached to the agreement.