Clinical trial NCT03048747
Conditions: Syndrome of Inappropriate Antidiuretic Hormone Secretion
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2017-03-02; Completion date: 2019-03-19
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study is to investigate the efficacy and safety of tolvaptan based on the change in serum sodium concentration following administration of tolvaptan oral tablets at 7.5 to 60 mg/day for up to 30 days in patients with hyponatremia in the SIADH.

Detailed description:

Arms: arm 1: Tolvaptan tablets at 7.5, 15, 30 (one tablet each), or 60 mg (two 30 mg tablets) will be orally administered once daily after breakfast for up to 30 days.
Interventions: intervention 1: Tolvaptan Oral Tablet
Intervention descriptions: intervention 1: Tolvaptan tablets at 7.5, 15, 30 (one tablet each), or 60 mg (two 30 mg tablets) will be orally administered once daily after breakfast for up to 30 days.

Protocol documents:
Prot_001.pdf: 
Protocol 156-14-003 
1 
Confidential - Proprietary Information 
Version 6.0, 15 May 2018 
Translation on 28 Mar 2019 
 
 
 
 
CLINICAL  STUDY  PROTOCOL 
 
 
A Multicenter, Uncontrolled, Open-label, Dose-titration Trial to 
Investigate the Efficacy and Safety of Tolvaptan Tablets in Patients 
With Hyponatremia in Syndrome of Inappropriate Antidiuretic 
Hormone Secretion (SIADH) 
 
                                                      NCT Number: 03048747 
 
                                                      Protocol No. 156-14-003 
 
                                     PRT Version Date: 15 May 2018（Version 6.0） 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 156-14-003 
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Otsuka Pharmaceutical Co., Ltd. 
Investigational Medicinal Product 
Tolvaptan (OPC-41061) 
CLINICAL PROTOCOL 
A Multicenter, Uncontrolled, Open-label, Dose-titration Trial to Investigate the Efficacy 
and Safety of Tolvaptan Tablets in Patients With Hyponatremia in Syndrome of 
Inappropriate Antidiuretic Hormone Secretion (SIADH) 
 
Protocol No. 156-14-003 
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_156-14-003@otsuka.jp 
 
Issue Date: 
13 Sep 2016 
Amendment 1 
19 Oct 2016 
Amendment 2 
29 Mar 2017 
Amendment 3 
23 Jun 2017 
Amendment 4 
14 Nov 2017 
Amendment 5 
15 May 2018 
 
Version No.: 
6.0 
 
Date of Translation: 
28 Mar 2019 


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Protocol Synopsis 
 
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd. 
Name of Investigational Medicinal Product: 
Tolvaptan (OPC-41061) 
Protocol No.: 156-14-003 
Protocol Title: 
A multicenter, uncontrolled, open-label, dose-titration trial to 
investigate the efficacy and safety of tolvaptan tablets in 
patients with hyponatremia in syndrome of inappropriate 
antidiuretic hormone secretion (SIADH) 
Clinical Phase/Trial 
Type: 
Phase 3 
Treatment Indication: SIADH 
Objective(s): 
To determine the efficacy and safety of tolvaptan based on the 
change in serum sodium concentration following 
administration of tolvaptan oral tablets at 7.5 to 60 mg/day for 
up to 30 days in Japanese patients with hyponatremia in 
SIADH 
Trial Design: 
A multicenter, uncontrolled, open-label, dose-titration clinical 
trial 
Subject Population: 
Total of 16 subjects with central measurement value for serum 
sodium concentration of <135 mEq/L at predose on Day 1 of 
the treatment period are to be treated with investigational 
medicinal product (IMP) 
At least 50% (8/16) of the above subjects should comprise 
subjects with serum sodium concentration of <130 mEq/L at 
predose on Day 1 of the treatment period. In addition, the 
number of subjects with SIADH due to ectopic antidiuretic 
hormone-producing tumors and the number of subjects with 
SIADH due to other causes should not be notably different. 
Inclusion/Exclusion 
Criteria: 
[Inclusion criteria] 
1) Subjects with a definite diagnosis of SIADH in reference 
to “Diagnostic and Treatment Manual of the 
Hypersecretion of Vasopressin (SIADH), Revised in 2011” 
(Appendix 1) 
2) Subjects who have been on fluid restriction (total daily 
fluid intake of ≤20 mL/kg body weight) for at least 7 
consecutive days at the time of informed consent and who 
are showing no improvement of hyponatremia (serum 
sodium concentration of <135 mEq/L) at the time of the 
screening examination. 
3) Subjects who have been on fluid restriction from the time 


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of the screening examination until the pretreatment 
observation (day before start of IMP administration) but 
whose serum sodium concentration at both the 
pretreatment observation and at predose on Day 1 of the 
treatment period is <135 mEq/L and increased by 
<5 mEq/L compared with that at the screening examination 
4) Male and female Japanese subjects age 20 to 85 years, 
inclusive, at the time of informed consent 
5) Subjects from whom informed consent can be obtained 
before start of the trial 
[Exclusion criteria] 
1) Subjects who have transient hyponatremia induced by drug 
administration 
2) Subjects with dehydration 
3) Subjects with hyponatremia due to heart failure, ascites 
associated with hepatic cirrhosis, or nephrotic syndrome 
4) Subjects with SIADH due to unknown etiology 
5) Subjects with substantial sodium transudation due to renal 
sodium loss, diarrhea, or vomiting 
6) Subjects who are unable to sense thirst or who have 
difficulty with fluid intake 
7) Subjects who have impaired consciousness (coma or 
stupor) 
8) Subjects who have AST (GOT) or ALT (GPT) exceeding 3 
times the upper limit of normal at the screening 
examination 
9) Subjects who have a history of myocardial infarction 
within 30 days prior to informed consent 
10) Subjects who have a history of persistent ventricular 
tachycardia or ventricular fibrillation despite having an 
implantable cardioverter defibrillator within 30 days prior 
to informed consent 
11) Subjects with decubitus angina, exertional angina induced 
by even mild exertion, or severe angina such as unstable 
angina 
12) Subjects with a history of cerebrovascular disorder within 
30 days prior to informed consent 
13) Subjects with a severe psychiatric disorder 
14) Subjects with systolic blood pressure of <90 mmHg at the 
time of the screening examination or at the pretreatment 
observation on the day before start of IMP administration 
15) Subjects with a history of hypersensitivity or idiosyncratic 


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reaction to benzazepine or benzazepine derivatives such as 
benazepril 
16) Subjects with a history of drug abuse within 1 year prior to 
informed consent or with current alcohol dependence 
17) Subjects with poorly controlled diabetes mellitus, defined 
as fasting blood glucose level of >300 mg/dL 
18) Subjects with urinary tract obstruction 
19) Subjects who have participated in any other clinical trial 
within 30 days prior to informed consent 
20) Subjects who have participated in another clinical trial of 
tolvaptan or who have previously received tolvaptan 
21) Subjects who are in the terminal stage of the disease or in a 
moribund state with an expected survival of less than 3 
months as judged by the investigator or subinvestigator 
22) Subjects with serum sodium concentration of <120 mEq/L 
associated with neurologic impairment, including apathy, 
confusion, or seizures 
23) Subjects with a progressive or episodic neurological 
disorder, including multiple sclerosis or with a history of 
multiple strokes 
24) Subjects with acute or transient hyponatremia due to head 
trauma or postoperative condition 
25) Subjects who are receiving intravenous infusion fluid at a 
keep-vein-open (KVO) volume (at the minimum fluid 
volume for preventing blood clots after the planned volume 
of fluid infusion) or higher 
26) Subjects with hyponatremia due to an artifact in laboratory 
tests (eg, a high blood glucose level of >300 mg/dL) 
27) Subjects who are receiving arginine vasopressin (AVP) or 
an AVP analog for the treatment of the disease 
28) Subjects who receive any other drugs for the treatment of 
hyponatremia, including demeclocycline, lithium 
carbonate, or urea within 7 days prior to start of IMP 
administration 
29) Subjects who have concomitantly used hypertonic saline 
for correction of serum sodium concentration within 7 days 
prior to informed consent or who are likely to require 
intravenous hypertonic saline infusion for correction of 
symptomatic or asymptomatic severe hyponatremia during 
the trial period 
30) Subjects with severe pulmonary hypertension: subjects 
whose disease state could be expected to worsen due to 
sudden changes in body fluid volume and blood pressure 


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31) Female subjects who are breast-feeding at the planned start 
of IMP administration or who are judged by the 
investigator or subinvestigator to be possibly pregnant 
based on the results of the pregnancy test at the screening 
examination. 
32) Male subjects or female subjects of childbearing potential 
who are sexually active and who do not agree to practice 
birth control as specified or to remain abstinent during the 
trial and until 30 days after final IMP administration 
Trial Site(s): 
Approximately 20 trial sites in Japan 
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration: 
Tolvaptan tablets at 7.5, 15, 30 (one tablet each), or 60 mg 
(two 30 mg tablets) will be orally administered once daily after 
breakfast for up to 30 days. The dose will be titrated in 
sequential order from 7.5 mg as the starting dose until the 
individual maintenance dose suitable for each subject is 
determined. 
Trial Assessments: 
Efficacy: Serum sodium concentration and clinical symptoms 
associated with hyponatremia 
Pharmacokinetics: Plasma concentrations of tolvaptan and its 
metabolites DM-4103 and DM-4107 
Pharmacodynamics: Daily urine volume, daily fluid intake, 
daily fluid balance, urine osmolality, serum osmolality, daily 
urinary sodium excretion, and plasma AVP concentration 
Safety: Adverse events (AEs), clinical laboratory tests, body 
weight, vital signs, 12-lead electrocardiography, liver function 
tests (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], and serum total bilirubin), and 
pregnancy test 
Criteria for 
Evaluation: 
Primary endpoint: 
 Percentage of subjects with normalized serum sodium 
concentration (≥135 mEq/L) on the day after final IMP 
administration 
Secondary endpoints: 
 Change in serum sodium concentration 
 Time course of serum sodium concentration 
 Changes in clinical symptoms associated with 
hyponatremia 
Statistical Methods: 
The efficacy analysis set and the maintenance dose-setting set 
will be analyzed as described below. Efficacy will be 


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comprehensively evaluated based on the following analysis 
and on individual subject data. 
Primary endpoint: 
 Percentage of subjects with normalized serum sodium 
concentration on the day after final IMP administration 
The percentage of subjects with normalized serum sodium 
concentration, defined as ≥135 mEq/L, on the day after 
final IMP administration will be calculated versus the 
number of subjects with serum sodium concentration of 
<135 mEq/L at baseline on Day 1 of the treatment period. 
The number, percentage, and 95% confidence interval (CI) 
of subjects with normalized serum sodium concentration 
on the day of fixing the maintenance dose and on the day 
after final IMP administration will be calculated. The 
number and percentage of subjects will also be calculated 
for each timepoint after start of IMP administration. 
Secondary endpoints: 
 Change in serum sodium concentration 
The number of subjects and the mean, standard deviation, 
minimum, median, and maximum values and 95% CI for 
measured values for serum sodium concentration and the 
change from baseline (predose on Day 1 of the treatment 
period) on the day of fixing the maintenance dose and on 
the day after final IMP administration will be calculated. 
Descriptive statistics at each timepoint after start of IMP 
administration will also be calculated. 
 Time course of serum sodium concentration 
The individual time courses of measured values and 
changes from baseline for serum sodium concentration will 
be plotted. 
 Changes in clinical symptoms associated with 
hyponatremia 
Shift tables of the changes in clinical symptom gradings 
from baseline (pretreatment observation) to the day of 
fixing the maintenance dose and from baseline to the day 
after final IMP administration will be generated. Shift 
tables of the changes at each postdose timepoint will be 
generated in the same way. 


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Trial Duration: 
Trial period: Nov 2016 to Mar 2020 
Expected duration of trial participation for each subject: Up to 
54 days 
(1 to 13 days for screening, 1 day for pretreatment observation 
period, up to 30 days for treatment period, and 7 to 10 days for 
follow up) 


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Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ........................................................................................... 8 
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 ........................................................................................ 19 
1.1 
Nonclinical Data ................................................................................................ 20 
1.2 
Clinical Data ......................................................................................................21 
1.2.1 
Foreign Phase 3 Trials (156-02-235, 156-03-238) .........................................21 
1.2.2 
Subgroup Analyses in Subjects With Syndrome of Inappropriate 
Secretion of Antidiuretic Hormone in Phase 3 Trials (156-02-235, 156- 
03-238)............................................................................................................21 
1.3 
Known and Potential Risks and Benefits .......................................................... 22 
2 
Trial Rationale and Objectives. ......................................................... 23 
2.1 
Trial Rationale ................................................................................................... 23 
2.2 
Dosing Rationale ............................................................................................... 24 
2.3 
Trial Objective ................................................................................................... 25 
3 
Trial Design ......................................................................................... 25 
3.1 
Type/Design of Trial ......................................................................................... 25 
3.2 
Trial Treatments ................................................................................................28 
3.2.1 
Dosage Regimen ............................................................................................. 28 
3.2.2 
Dose Escalation Criteria .................................................................................28 
3.2.3 
Criteria for Maintenance Dose Determination ...............................................29 
3.2.4 
Treatment Period ............................................................................................ 29 
3.2.5 
Hospitalization ................................................................................................ 30 
3.3 
Trial Population ................................................................................................. 31 
3.3.1 
Number of Subjects and Description of Population .......................................31 
3.3.2 
Subject Identification Number ........................................................................31 
3.4 
Eligibility Criteria .............................................................................................. 31 
3.4.1 
Informed Consent ...........................................................................................31 


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3.4.2 
Inclusion Criteria ............................................................................................ 32 
3.4.3 
Exclusion Criteria ........................................................................................... 33 
3.5 
Endpoints ........................................................................................................... 35 
3.5.1 
Efficacy ...........................................................................................................35 
3.5.1.1 
Primary Endpoint ........................................................................................35 
3.5.1.2 
Secondary Endpoints ...................................................................................36 
3.5.2 
Pharmacodynamics ........................................................................................ 36 
3.5.3 
Pharmacokinetics ............................................................................................ 36 
3.5.4 
Safety .............................................................................................................. 36 
3.6 
Measures to Minimize/Avoid Bias ....................................................................36 
3.7 
Trial Procedures ................................................................................................36 
3.7.1 
Schedule of Assessments ................................................................................43 
3.7.1.1 
Screening Period (14 to 2 Days Before Start of IMP Administration) ....... 43 
3.7.1.2 
Screening Period (2 Days Before Start of IMP Administration) ................ 45 
3.7.1.3 
Pretreatment Observation Period (Day Before Start of IMP 
Administration) ........................................................................................... 45 
3.7.1.4 
Day 1 of Treatment Period .......................................................................... 46 
3.7.1.5 
Day 2 of Treatment Period .......................................................................... 47 
3.7.1.6 
Day 3 of Treatment Period .......................................................................... 48 
3.7.1.7 
Day 4 of Treatment Period .......................................................................... 50 
3.7.1.8 
Day 5 of Treatment Period .......................................................................... 51 
3.7.1.9 
Day 6 of Treatment Period .......................................................................... 52 
3.7.1.10 
Day 7 of Treatment Period .......................................................................... 53 
3.7.1.11 
Days 8 to 10 of Treatment Period ...............................................................55 
3.7.1.12 
Day 14 of Treatment Period ........................................................................55 
3.7.1.13 
Day 21 of Treatment Period ........................................................................56 
3.7.1.14 
Day After the Final IMP Administration .................................................... 57 
3.7.1.15 
Procedures to Be Performed Until the Maintenance Dose Is 
Determined ..................................................................................................58 
3.7.1.16 
When the Maintenance Dose of the IMP Is Determined ........................... 59 
3.7.1.17 
When Switching to Outpatient Treatment ................................................... 60 
3.7.1.18 
Change in the Maintenance Dose of the IMP ............................................ 60 
3.7.1.19 
Treatment Discontinuation ..........................................................................61 


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3.7.1.20 
Follow-up ....................................................................................................62 
3.7.1.20.1 
Serum Sodium Concentration (3 to 5 Days After the Final IMP 
Administration) ........................................................................................ 62 
3.7.1.20.2 
Follow-up Examination (7 to 10 Days After the Final IMP 
Administration) ........................................................................................ 62 
3.7.2 
Efficacy Assessments ..................................................................................... 63 
3.7.2.1 
Serum Sodium Concentration ..................................................................... 63 
3.7.2.2 
Clinical Symptoms Associated With Hyponatremia. .................................. 63 
3.7.3 
Safety Assessments .........................................................................................65 
3.7.3.1 
Adverse Events............................................................................................ 65 
3.7.3.2 
Clinical Laboratory Tests ............................................................................ 65 
3.7.3.3 
Body Weight ............................................................................................... 67 
3.7.3.4 
Vital Signs ...................................................................................................67 
3.7.3.4.1 
Body Temperature ...................................................................................67 
3.7.3.4.2 
Blood Pressure and Pulse Rate ................................................................67 
3.7.3.5 
12-Lead Electrocardiography ...................................................................... 67 
3.7.3.6 
Pregnancy Test ............................................................................................67 
3.7.4 
Pharmacokinetic/Pharmacodynamic Assessments ......................................... 68 
3.7.4.1 
Pharmacokinetic Assessments .................................................................... 68 
3.7.4.1.1 
Pharmacokinetic Blood Samples .............................................................68 
3.7.4.2 
Pharmacodynamic Assessments..................................................................68 
3.7.4.2.1 
Daily Urine Volume ................................................................................ 68 
3.7.4.2.2 
Daily Fluid Intake .................................................................................... 69 
3.7.4.2.3 
Daily Fluid Balance .................................................................................69 
3.7.4.2.4 
Serum Osmolality .................................................................................... 69 
3.7.4.2.5 
Urine Osmolality .....................................................................................70 
3.7.4.2.6 
Daily Urinary Sodium Excretion ............................................................. 70 
3.7.4.2.7 
Plasma Arginine Vasopressin Concentration .......................................... 71 
3.7.5 
End of the Trial ...............................................................................................71 
3.8 
Discontinuation Criteria and Procedures ...........................................................71 
3.8.1 
Entire Trial ..................................................................................................... 71 
3.8.2 
Individual Trial Sites ...................................................................................... 71 
3.8.3 
Individual Subject Discontinuation ................................................................ 72 


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3.8.3.1 
Treatment Discontinuation ..........................................................................72 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation ...............................72 
3.8.3.3 
Withdrawal of Consent ...............................................................................73 
3.8.3.4 
Procedures to Encourage Continued Trial Participation .............................74 
3.9 
Screen Failure ....................................................................................................74 
3.10 
Definition of Completed Subjects .....................................................................75 
3.11 
Definition of Subjects Lost to Follow-up .......................................................... 75 
3.12 
Subject Compliance ...........................................................................................76 
3.13 
Protocol Deviations ........................................................................................... 76 
3.14 
Investigation of Treatment Compliance ............................................................77 
4 
Restrictions .......................................................................................... 77 
4.1 
Prohibited Concomitant Medications ................................................................ 77 
4.2 
Fluid Intake Restriction ..................................................................................... 79 
5 
Reporting of Adverse Events ............................................................. 79 
5.1 
Definition.......................................................................................................... 79 
5.2 
Eliciting and Reporting Adverse Events ...........................................................81 
5.3 
Immediately Reportable Events ........................................................................82 
5.4 
Potential Drug-Induced Liver Injury .................................................................83 
5.5 
Pregnancy ..........................................................................................................83 
5.6 
Procedure for Breaking the Blind ..................................................................... 84 
5.7 
Follow-up of Adverse Events ............................................................................84 
5.7.1 
Follow-up of Nonserious Adverse Events ......................................................85 
5.7.2 
Follow-up of Serious Adverse Events ............................................................85 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring After 
the Trial Completion Day ...............................................................................85 
6 
Pharmacokinetic/Pharmacodynamic Analysis ................................ 86 
6.1 
Pharmacokinetic Analysis .................................................................................86 
6.2 
Pharmacodynamic Analysis ..............................................................................86 
7 
Statistical Analysis .............................................................................. 86 
7.1 
Sample Size .......................................................................................................86 
7.2 
Datasets for Analysis .........................................................................................88 
7.2.1 
Efficacy Analysis Set ..................................................................................... 88 
7.2.2 
Maintenance Dose-setting Set ........................................................................88 


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7.2.3 
Safety Analysis Set .........................................................................................88 
7.2.4 
Pharmacokinetic Analysis Set ........................................................................88 
7.2.5 
Pharmacodynamic Analysis Set .....................................................................88 
7.3 
Handling of Missing Data ................................................................................. 88 
7.4 
Primary and Secondary Endpoint Analyses ..................................................... 88 
7.4.1 
Primary Endpoint Analysis ............................................................................ 89 
7.4.2 
Secondary Endpoint Analyses ........................................................................89 
7.4.2.1 
Change in Serum Sodium Concentration .................................................... 89 
7.4.2.2 
Time Course of Serum Sodium Concentration ........................................... 90 
7.4.2.3 
Changes in Clinical Symptoms Associated With Hyponatremia ................90 
7.5 
Analyses of Demographic and Baseline Characteristics .................................. 90 
7.6 
Safety Analysis ..................................................................................................90 
7.6.1 
Adverse Events ...............................................................................................90 
7.6.2 
Clinical Laboratory Tests................................................................................ 91 
7.6.3 
Body Weight and Vital Signs ......................................................................... 91 
7.6.4 
12-Lead Electrocardiography ......................................................................... 91 
7.6.5 
Liver Function Tests .......................................................................................92 
8 
Management of Investigational Medicinal Products ...................... 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 .........................................................93 
8.5.1 
Eliciting and Reporting Product Quality Complaints ..................................... 93 
8.5.2 
Information Required for Reporting Purposes ...............................................93 
8.5.3 
Return Process ................................................................................................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 


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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 .......................................................................... 33 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 34 
Table 3.7-1 
Schedule of Assessments (1/2) ..................................................... 37 
Table 3.7.3.2-1 
Clinical Laboratory Assessments .................................................. 66 
Table 4.1-1 
List of Medications Prohibited During the Trial ........................... 78 
Table 4.1-2 
Drugs and Foods That May Be Strong Inhibitors or Inducers 
of CYP3A4.................................................................................... 78 


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List of In-text Figures 
Figure 3.1-1 
Trial Design .................................................................................. 27 
Figure 3.1-2 
Trial Flowchart.............................................................................. 27 


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List of Appendices 
Appendix 1 
Diagnostic and Treatment Manual of the Hypersecretion of 
Vasopressin (SIADH), Revised in 2011 ..................................... 101 
Appendix 2 
Handling and Shipment of Pharmacokinetic Blood Samples ..... 103 
Appendix 3 
Procedure for Readministration with the IMP ............................ 104 
Appendix 4 
Protocol Amendments/Administrative Changes ......................... 107 


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List of Abbreviations and Definitions of Terms 
Abbreviation Definition 
ADL 
Activities of daily living 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AVP 
Arginine vasopressin 
CI 
Confidence interval 
CNS 
Central nervous system 
CRF 
Case report form 
CYP 
Cytochrome P450 
DDAVP 
1-deamino-8-D-arginine vasopressin 
DILI 
Drug Induced Liver Injury 
EU 
European Union 
GCP 
Good Clinical Practice 
GOT 
Glutamic-oxaloacetic transaminase 
GPT 
Glutamic-pyruvic transaminase 
hCG 
Human chorionic gonadotropin 
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 
KVO 
Keep Vein Open 
MedDRA 
Medical Dictionary for Regulatory Activities 
OPC 
Otsuka Pharmaceutical Co., Ltd. 
PQC 
Product quality complaint 
SAE 
Serious adverse event 
SIADH 
Syndrome of inappropriate secretion of antidiuretic hormone 
TEAE 
Treatment-emergent adverse event 
QOL 
Quality of life 
ULN 
Upper limit of normal 
US 
United States 


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Definitions of Terms 
 
Term 
Definition 
Screen failure 
A patient who provided informed consent but received no IMP 
Trial start date for each 
subject 
Date of obtaining signed informed consent from each subject 
Trial discontinuation 
date for each subject 
Date on which the investigator or subinvestigator decided to 
withdraw the subject from the trial, or date of the examination 
at discontinuation, whichever comes later 
Trial completion date 
for each subject 
Trial discontinuation date, or date of the follow-up 
examination, whichever comes later 
If 2 or more follow-up examinations were performed, the date 
of the last examination will be considered as the trial 
completion date 
Trial period for each 
subject 
Period from the date of obtaining signed informed consent to 
the trial completion date 


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1 
Introduction 
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a disease state 
in which vasopressin is inappropriately released beyond the physiological regulatory 
mechanism, due to various underlying diseases. The causes of SIADH can be roughly 
classified into the following 2 types: cases due to the ectopic production of vasopressin 
(ie, ectopic vasopressin producing tumors [malignant tumors]) and cases due to excess 
endogenous vasopressin secretion associated with central nervous system (CNS) 
disorders and pulmonary diseases.1 
Inappropriately secreted vasopressin causes water retention by increasing water 
reabsorption at the renal collecting duct through the V2 receptor, thereby suppressing 
water clearance from the kidney, which results in dilutional hyponatremia. In mild cases, 
dilutional hyponatremia may be asymptomatic; however, if left untreated, it may 
gradually worsen, and present with neurological symptoms (appetite impaired, headache, 
somnolence, nausea, vomiting, coma, and convulsions) as the condition progresses, 
ultimately resulting in fatal cerebral edema.2 
The purpose of treatment of SIADH is to correct the low sodium levels, improve the CNS 
symptoms, and prevent cerebral edema. For this purpose, elimination of the cause (eg, 
treatment of the underlying disease) is the first priority. However, as the underlying 
disease may not be improved, or the symptoms of SIADH may be prolonged after 
treatment of the underlying disease, palliative therapy is the mainstay for the treatment of 
hyponatremia. In general, fluid restriction is the treatment of choice for hyponatremia, 
regardless of the underlying disease; however, fluid restriction commonly has a delayed 
onset of effect, hinders treatment of the underlying disease, and impairs patient quality of 
life (QOL) due to severe thirst. Accordingly, patients with severe hyponatremia who 
require a rapid corrective action are generally treated with a combination of furosemide 
and hypertonic saline. This combination therapy eliminates excessive water by 
intravenous furosemide and supplements sodium loss by hypertonic saline, which may 
cause a rapid elevation of the serum sodium concentration; therefore, the therapy must be 
administered with extreme caution. In addition, this therapy is of limited use, as it 
involves intravenous injection and intravenous infusion.3 
Tolvaptan is a nonpeptidic, cAMP-dependent arginine vasopressin (AVP) V2-receptor 
antagonist discovered by Otsuka Pharmaceutical Co., Ltd. It inhibits water reabsorption 
at the renal collecting duct, thereby enhancing water diuresis without depletion of 
electrolytes. Tolvaptan was approved in the United States (US) in May 2009 for the 
treatment of clinically significant hypervolemic and euvolemic hyponatremia, including 


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patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone 
(SIADH), etc., and in the European Union (EU) in August 2009 for the treatment of 
hyponatremia secondary to SIADH in adults. The recommended starting dose is 15 mg 
once daily, which may be increased to a maximum of 60 mg once daily. 
In Japan, tolvaptan was approved on 27 Oct 2010 under the brand name, “Samsca Tablets 
15 mg” for “the treatment of volume overload in heart failure when adequate response is 
not obtained with other diuretics (eg, loop diuretics)” (also approved as “Samsca Tablets 
7.5 mg” on 04 Feb 2013 for the same indication). It was then approved on 13 Sep 2013 as 
“Samsca Tablets 7.5 mg” for “the treatment of fluid retention in hepatic cirrhosis when 
adequate response is not obtained with other diuretics (eg, loop diuretics).” The 
indications of tolvaptan were further expanded on 24 Mar 2014 under the brand name, 
“Samsca Tablets 7.5 mg, 15 mg, and 30 mg” to include “suppression of progression of 
autosomal dominant polycystic kidney disease (ADPKD) in patients with increased 
kidney volume and a rapid rate of increase.” 
In December 2013, the Japan Endocrine Society made a development request of 
tolvaptan to the Ministry of Health, Labour and Welfare for the treatment of 
improvement of hyponatremia secondary to SIADH as an unapproved and off-label drug 
of high medical need. The Study Group on Unapproved and Off-label Drugs of High 
Medical Need accepted the request at the 23th Investigational Committee held on 22 Apr 
2015, and requested for the company to develop the drug for the indication of 
improvement of hyponatremia secondary to SIADH, as an unapproved and off-label drug 
of high medical need (MHLW/HPB/RDD Notification No. 0521-1 and PFSB/ELD 
Notification 0521-1, dated 21 May 2015). Subsequently, at the 24th Investigational 
Committee held on 14 Oct 2015, the Study Group determined that a Japanese clinical 
trial should be conducted to demonstrate the appropriateness of the proposed dosage 
regimen (the efficacy and safety of tolvaptan administered at the proposed dosage 
regimen), and to confirm the safety and other characteristics of the drug under a specified 
monitoring. Accordingly, the present clinical trial was planned. 
1.1 
Nonclinical Data 
 
The effects of tolvaptan on hyponatremia were evaluated in rat acute and chronic models 
of hyponatremia. In the rat model of acutely progressive hyponatremia, combined 
treatment of subcutaneous infusion (10 ng/hr subcutaneous [SC]) of [deamino-Cys1, 
DArg8]-vasopressin (DDAVP), a peptide V2 agonist and water loading progressively 
decreased plasma sodium concentration, resulting in severe hyponatremia associated with 
high mortality. In this acute hyponatremia model, oral doses of tolvaptan at 1, 3, and 


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10 mg/kg induced dose-dependent aquaresis, leading to an increase in plasma sodium 
concentration and a reduction in mortality rate. In the rat model of chronic hyponatremia 
induced by DDAVP infusion (1 ng/hr SC) and liquid diet, plasma sodium concentration 
was reduced to about 110 mEq/L and maintained at that level without any deaths. In this 
chronic hyponatremia model, oral doses of tolvaptan at ascending concentrations from 
0.25 to 8 mg/kg nearly normalized the plasma sodium concentration, and improved the 
wet kidney weight and water content in the brain and heart, which had been increased by 
chronic hyponatremia. These results suggested the potential of tolvaptan in the treatment 
of hyponatremia. 
For detailed nonclinical data, see the Investigator’s Brochure (IB). 
1.2 
Clinical Data 
 
Among the results of phase 3 trials conducted in the US and EU (156-02-235, 156-03- 
238),4 as well as those of the subgroup analyses, data from 110 patients with 
hypernatremia whose underlying disease was diagnosed as SIADH5 are presented below. 
For detailed information on these trials, see the IB. 
1.2.1 
Foreign Phase 3 Trials (156-02-235, 156-03-238) 
 
Results from 416 evaluable subjects with euvolemic or hypervolemic hyponatremia 
(serum sodium <135 mEq/L) resulting from a variety of underlying causes (eg, heart 
failure, liver cirrhosis, SIADH, etc.), who were treated for 30 days with tolvaptan (titrated 
dose) or placebo in the phase 3 trials (156-02-235, 156-03-238) conducted in the US and 
EU demonstrated that: 
 The average daily area under the concentration-time curve (AUC) for the change in 
serum sodium from baseline to Day 4 and from baseline to Day 30 (the primary 
endpoint) was significantly greater in the tolvaptan group than in the placebo group 
(p < 0.0001), when adjusted for multiplicity associated with 2 assessment points. 
 A significantly higher serum sodium concentration was noted in the tolvaptan group 
than in the placebo group, from 8 hours after the first dose (the first assessment point 
after the start of treatment), which lasted for 30 days. 
 The serum sodium concentration in the tolvaptan group declined to a level similar to 
that in the placebo group, within 7 days after tolvaptan therapy was discontinued. 
 
1.2.2 Subgroup Analyses in Subjects With Syndrome of Inappropriate 
Secretion of Antidiuretic Hormone in Phase 3 Trials (156-02-235, 
156-03-238) 
 
Among the results of the subgroup analyses in phase 3 trials conducted in the US and EU 
(156-02-235, 156-03-238), data from 110 subjects with hypernatremia whose underlying 


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disease was diagnosed as SIADH (52 in the tolvaptan group, 58 in the placebo group) are 
presented below. 
 Forty-two subjects (80.8%) in the tolvaptan group and 42 subjects (72.4%) in the 
placebo group completed the treatment period of up to 30 days. Among these subjects, 
30 (57.7%) in the tolvaptan group and 29 (50.0%) in the placebo group had severe 
hyponatremia (serum sodium concentration <130 mmol/L). 
 The average daily AUC for the change in serum sodium concentration from baseline 
to Day 4 and from baseline to Day 30 (the primary endpoint) was 5.28 ± 3.35 mmol/L 
(mean ± standard deviation) in the tolvaptan group and 0.47 ± 2.81 mmol/L in the 
placebo group on Day 4, and 8.07 ± 4.55 mmol/L in the tolvaptan group and 1.89 ± 
4.13 mmol/L in the placebo group on Day 30, which indicated a significant increase 
in the tolvaptan group, compared with the placebo group (p < 0.0001) at both 
assessment points. The serum sodium concentrations observed in the tolvaptan group 
were significantly higher than those in the placebo group at all of the time points. 
 The exposure was 1396 person-days in the tolvaptan group and 1425 person-days in 
the placebo group. Dry mouth and thirst, the most frequently reported adverse drug 
reactions (ADRs) in the treatment of tolvaptan, occurred respectively in 9 subjects 
(17.6%) and 8 subjects (15.7%) in the tolvaptan group, and 5 subjects (8.6%) and 6 
subjects (10.3%) in the placebo group. The incidences of dizziness, nausea, 
hypotension, and nasopharyngitis were slightly higher in the tolvaptan group than in 
the placebo group. A total of 4 subjects died, 1 subject in the tolvaptan group and 3 
subjects in the placebo group. 
 Among the 51 subjects treated with tolvaptan, 3 subjects developed a too rapid 
correction in serum sodium concentration, exceeding the upper limit of the serum 
sodium correction specified by the protocol (serum sodium increases ≥12 mmol/L 
within 24 hours or ≥18 mmol/L within 48 hours). Of these 3 subjects, 1 subject 
experienced a 13 mmol/L increase within 24 hours, and 2 subjects experienced a 
14 mmol/L increase within 24 hours. These 3 subjects had severe hyponatremia with 
a serum sodium concentration of <130 mmol/L at baseline, but no neurological signs 
suggestive of osmotic demyelination syndrome were reported. 
 
1.3 
Known and Potential Risks and Benefits 
 
In clinical trials involving patients with hyponatremia, the most frequently reported 
adverse events (AEs) with an incidence of >5% in 511 subjects treated with oral 
tolvaptan were thirst, dry mouth, oedema peripheral, nausea, dizziness, fatigue, 
constipation, headache, ascites, diarrhoea, pollakiuria, asthenia, hypotension, pyrexia, and 
hypokalaemia. The most frequently reported AEs with an incidence of >5% in subjects 
receiving placebo were oedema peripheral, diarrhoea, headache, ascites, vomiting, 
dyspnoea, nausea, and hypotension. The AEs with a higher incidence in subjects treated 
with tolvaptan than in subjects receiving placebo were thirst, dry mouth, nausea, 
dizziness, fatigue, constipation, pollakiuria, asthenia, hypotension, pyrexia, and 


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hypokalaemia. In 416 evaluable subjects with hyponatremia treated with tolvaptan in the 
phase 3 trials conducted in the US and EU (156-02-235, 156-03-238), serum sodium 
concentration improved continuously regardless of the underlying disease, and 
normalized in most subjects. For the details of the AEs attributable to tolvaptan therapy 
in clinical trials, see the latest IB. 
 
 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
 
The mechanism of the onset of hyponatremia in patients with SIADH is the abnormal 
regulation of nonosmotic AVP release.6 Hyponatremia in patients with SIADH is 
primarily treated with fluid restriction and hypertonic saline infusion. Fluid restriction has 
the advantage of correcting serum sodium concentration safely, but has a delayed onset of 
effect and is also difficult for patients to accept as an established therapy due to its poor 
tolerability. Hypertonic saline infusion has a rapid onset of effect, and is therefore 
appropriate in acute treatment; however, the sustained normalization of serum sodium 
concentration with a hypertonic saline infusion is difficult.7 The conventional treatments 
for hyponatremia are based on fluid restriction. Tolvaptan is expected to ease fluid 
restriction, thereby exerting its therapeutic effects rapidly as demonstrated by three phase 
3 trials conducted overseas, and improving QOL impaired by fluid restriction. Hypertonic 
saline infusion is an emergency treatment, and is not generally expected to be used 
concomitantly with tolvaptan. However, tolvaptan with a different administration route 
may be useful in outpatient management after the correction of serum sodium with 
hypertonic saline. Unlike mozavaptan, which is limited to the treatment of SIADH 
secondary to ectopic antidiuretic hormone-producing tumors, tolvaptan has been 
demonstrated in overseas clinical trials to be clinically effective and safe regardless of the 
underlying disease, and could be administered to all patients with SIADH. The 
demonstrated clinical efficacy and safety of tolvaptan are based on the outcome of 30-day 
treatment, while those of mozavaptan are based on the outcome of 7-day treatment. 
Tolvaptan is an ingestible AVP receptor antagonist with a high affinity for the V2 
receptor, and has been shown to produce water diuresis resulting in the increased 
excretion of free water. 
In the US and EU, tolvaptan is approved for the treatment of hyponatremia secondary to 
SIADH. However, the efficacy and safety of tolvaptan have not been demonstrated in 
Japanese patients. The present clinical trial was planned to demonstrate the 


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appropriateness of the proposed dosage regimen (the efficacy and safety of tolvaptan 
administered at the proposed dosage regimen), and to confirm the safety and other 
characteristics of the drug under a specified monitoring. This protocol was prepared 
based on the agreement reached with PMDA regarding the appropriateness of the trial 
plan at the consultation after completion of the phase 2 trial (19 Apr 2016, Application 
Number P3962). 
In the view of the above, the conduct of this trial is scientifically and ethically appropriate. 
2.2 
Dosing Rationale 
 
The approved dosage regimen of tolvaptan for the treatment of patients with 
hypernatremia, including those with SIADH, in the US and EU is “The starting dose is 
15 mg once daily, which may be increased to a maximum of 60 mg once daily.” The 
European Summaries of Product Characteristics (SmPC) states based on the results of 
clinical trials, that the frequency of rapid correction of hyponatremia is ≥1% to <10%; 
however, a higher incidence of 18.4% was observed in a post-marketing safety trial 
conducted in the EU (156-09-101),8 with no reports of neurological sequelae in all 
patients. In addition, the actual dose utilization data showed that 42.1% of patients treated 
with tolvaptan received at least 1 dose of 7.5 mg/day. Based on these results, the 
European authorities requested that the company investigate the possibility of a starting 
dose of 7.5 mg/day, and a clinical pharmacology trial (156-12-203)9 of the single 
administration of tolvaptan at 3.75, 7.5, and 15 mg to patients with SIADH was 
conducted in the EU. In this trial, for serum sodium concentration, either an increase of 
≥8 mEq/L at 8 hours postdose or an increase of ≥12 mEq/L at 24 hours postdose was 
observed in 4 of 28 patients: 1 patient (10 %) at 3.75 mg, 1 patient (10%) at 7.5 mg, and 2 
patients (25%) at 15 mg. Regarding safety, no relationship between dose and the 
incidence of the rapid correction of serum sodium was found. Regarding efficacy, the 
mean maximum increase in serum sodium concentration increased in a dose-dependent 
manner: 3.6 mmol/L in the 3.75 group, 5.3 mmol/L in the 7.5 mg group, and 7.9 mmol/L 
in the 15 mg group. The greatest median increase in serum sodium concentration was 
observed in the 7.5 mg group (6.0 mmol/L) as compared to the 3.75 and 15 mg group 
(2.5 mmol/L and 5.0 mmol/L, respectively). 
In the present clinical trial, in consideration of subject safety, the starting dose is set at 
7.5 mg/day, which is one half of the approved dose in the US and EU, with an increase in 
dose to 15 mg/day, followed by 30 mg/day and then 60 mg/day, according to the dose 
titration scheme to determine the optimal dose in each subject. 
Tolvaptan will be administered once daily after breakfast, as approved overseas. 


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2.3 
Trial Objective 
 
To determine the efficacy and safety of tolvaptan based on the change in serum sodium 
concentration following administration of tolvaptan oral tablets at 7.5 to 60 mg/day for up 
to 30 days in Japanese patients with hyponatremia in SIADH 
 
 
3 
Trial Design 
3.1 
Type/Design of Trial 
 
This clinical trial is a multicenter, uncontrolled, open-label, dose-titration trial to 
investigate the efficacy and safety of tolvaptan administered for up to 30 days at a dose of 
7.5 to 60 mg/day, based on the change in serum sodium concentration in Japanese 
patients with hyponatremia secondary to SIADH. The trial design schematic and trial 
flowchart are shown in Figure 3.1-1 and Figure 3.1-2. 
The trial consists of a screening period, pretreatment observation period, treatment period, 
and follow-up period. 
After written informed consent has been obtained, the investigator or subinvestigator will 
perform the screening examination to confirm the eligibility of the subject within 14 to 2 
days before start of IMP administration. The subject will be admitted to the trial site 2 
days before start of IMP administration, at which eligibility for trial entry is confirmed 
during the pretreatment observation (the day before start of IMP administration) and 
predose on Day 1 of the treatment period. 
From Day 1, the IMP will be orally administered once daily after breakfast, and the 
specified observations, examinations, and investigations will be performed for the 
efficacy and safety evaluations. The starting dose of the IMP is 7.5 mg/day, which will be 
increased to 15 mg/day, followed by 30 mg/day then 60 mg/day on or after Day 2, 
according to Section 3.2.2, to determine the maintenance dose in each subject as specified 
in Section 3.2.3. Once the maintenance dose has been determined, the IMP will be 
administered continuously at that dose throughout the period defined by Section 3.2.4, as 
a rule. 
If the subject becomes less responsive to the IMP due to exacerbation of the underlying 
disease or other causes, and the investigator or subinvestigator concludes that dose 
escalation is needed and this increase would raise no safety problems, the dose may be 
increased. When increasing the dose beyond the maintenance dose once it has been 
determined, the subject should be hospitalized at the trial site to determine a new 
maintenance dose according to Section 3.2.2. 


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To prevent a too rapid increase in serum sodium concentration, fluid restriction should be 
avoided within 24 hours after IMP administration on Day 1 of the treatment period, based 
on safety considerations. From Day 2 of treatment period and onward, the investigator or 
subinvestigator will define the upper limit of daily fluid intake for the subject according 
to Section 4.2, and instruct the subject to take fluids depending on his/her condition. 
From the day after the maintenance dose has been determined and onward, a decision 
regarding switching the subject to outpatient treatment will be made as specified in 
Section 3.2.5. 
The maximum treatment duration is 30 days. If the serum sodium concentration has 
normalized (≥135 mEq/L), the subject has no subjective symptoms associated with 
hyponatremia, and the investigator or subinvestigator concludes that the serum sodium 
concentration is unlikely to decrease on withdrawal of the IMP, the treatment may be 
completed before the duration of treatment reaches 30 days. 
The subject should visit the trial site 7 to 10 days after the completion of IMP treatment 
to undergo the follow-up examination. Since serum sodium concentration is expected to 
decrease due to the withdrawal of treatment, serum sodium concentration will be 
measured 3 to 5 days after completion of IMP treatment. 
If hyponatremia recurs after treatment with the IMP has been completed before the 
duration of treatment reached 30 days (except treatment discontinuations as specified in 
Section 3.8.3.1), and it is judged by the investigator or subinvestigator that 
readministration with the IMP is necessary, treatment may be resumed within 30 days 
after the initial IMP administration (for the readministration procedure, see Appendix 3). 
The trial participation period for each subject is from the date of signed informed consent 
to the trial completion date. 
Definition of trial completion date: 
The trial completion date is defined as the trial discontinuation date, or the date on which 
the follow-up examination is completed, whichever comes later (If 2 or more follow-up 
examinations were performed, the date of the last examination will be taken as the trial 
completion date.) 


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← Serum sodium measurement 
 
 
 
Screening 
period 
Pretreatment 
observation 
period 
7.5 mg 
Treatment period (up to 30 days) 
60 mg 
30 mg 
15 mg 
Follow-up 
period 
−14  to −2 
−1 
1 
 
Maintenance dose should be determined individually until Day 10. 
7 to 10 days after the completion 
of IM P treatment 
 
3 to 5 days after the completion 
of IM P treatment 
 
 
 
 
 
 
 
Figure 3.1-1 
Trial Design 
 
 
Figure 3.1-2 
Trial Flowchart 
a 
Dose escalation should be completed to determine the maintenance dose by Day 10 (see Section 3.2.1, 
Section 3.2.2, and Section 3.2.3) 
b 
The IMP will be administered in an inpatient or outpatient setting. 
c 
If readministration with the IMP is needed, at the discretion of the investigator or subinvestigator, the 
subject may visit the trial site after the initial follow-up examination is completed to undergo the 
second follow-up examination. 
d 
Treatment with the IMP may be resumed within 30 days after the initial IMP administration (see 
Appendix 3). 
Follow-up examination for 
the measurement of 
serum sodium concentration
c
 
Screening period and 
pretreatment observation 
period 
Treatment period 
(up to 30 days from the initial IMP administration to the completion of   treatment) 
Follow-up period 
In  an  inpatient setting 
→  Start of treatment   →   
Dose escalation    
→ 
(see  Section 3.2.2) 
Determination 
of maintenance → 
dosea 
End of 
→ 
→ 
→ the trial 
Hospitalization (2 days 
Switching to outp atient treatment 
before the start of treatment) 
Dose increased beyond the maintenance dose, 
once determined 
If readministration is started 
Screening examination 
Treatment 
continued
b
 
Completion 
of treatment 
Readministration
d
 
← Follow-up examination 
← Informed consent 


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3.2 
Trial Treatments 
 
3.2.1 
Dosage Regimen 
 
Subjects will take tolvaptan tablets once daily after breakfast with water. 
The starting dose of tolvaptan is 7.5 mg/day (one 7.5 mg tablet), which will be increased 
to 15 mg/day (one 15 mg tablet) on or after Day 2 of treatment period, followed by 
30 mg/day (one 30 mg tablet) and then 60 mg/day (two 30 mg tablets), as specified in 
Section 3.2.2 to determine the maintenance dose for each subject, according to 
Section 3.2.3. Once the maintenance dose has been determined, the IMP will be 
administered continuously at that dose throughout the period defined by Section 3.2.4, as 
a rule. 
The dose may be reduced at any time during the treatment period, if any safety problem 
arises and the investigator or subinvestigator concludes that a dose reduction is necessary. 
Dose reduction should be performed as 1 dose level per day. 
If the subject becomes less responsive to the IMP due to exacerbation of underlying 
disease or other causes, and the investigator or subinvestigator concludes that dose 
escalation is needed and that this increase would raise no safety problems, the dose may 
be increased. When increasing the dose beyond the maintenance dose once it has been 
determined, the subject should be hospitalized at the trial site to determine a new 
maintenance dose according to Section 3.2.2. 
The serum sodium concentrations used to determine whether the subject meets the 
criteria for dose escalation, maintenance dose, and switching to outpatient treatment 
(Section 3.7.1.17) will be based on serum sodium concentrations measured at each trial 
site. 
3.2.2 
Dose Escalation Criteria 
 
1) Day 2 of treatment period 
If the predose serum sodium concentration meets both of the criteria below, the dose 
will be increased to 15 mg/day. 
 The serum sodium concentration is <130 mEq/L. 
 The increase in serum sodium concentration from predose on Day 1 is <5 mEq/L. 
Even if both of these criteria are met, the same dose as that administered on Day 1 
should be administered, if the investigator or subinvestigator concludes that dose 
escalation is inappropriate due to safety concerns. 


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2) From Day 3 of treatment period and onward 
If the predose serum sodium concentration meets both of the criteria below, the dose 
will be increased. 
 The serum sodium concentration is <135 mEq/L. 
 The increase in serum sodium concentration from predose on the previous day is 
<5 mEq/L. 
Even if both of these criteria are met, the same dose as that administered on the 
previous day should be administered when any of the following are present on the day 
that dose escalation is determined: 
 The dose was increased on the previous day, and the predose serum sodium 
concentration on the day dose escalation is assessed is ≥130 mEq/L and 
<135 mEq/L; OR 
 The serum sodium concentration has increased continuously during the previous 2 
days and is expected to increase further without dose escalation, at the discretion 
of the investigator or subinvestigator; OR 
 The investigator or subinvestigator concludes that dose escalation is inappropriate 
due to safety concerns. 
 
3.2.3 
Criteria for Maintenance Dose Determination 
 
The maintenance dose will be determined if any of the following criteria are met. 
 The serum sodium concentration has normalized (≥135 mEq/L) 
 Further dose escalation is considered to be inappropriate due to safety concerns. 
 The dose of the IMP has reached 60 mg/day. 
 None of the above criteria have been met up to Day 10 of the treatment period. 
 
3.2.4 
Treatment Period 
 
The maximum treatment duration with the IMP is 30 days. If the serum sodium 
concentration normalizes (≥135 mEq/L), the subject has no subjective symptoms 
associated with hyponatremia, and the investigator or subinvestigator concludes that the 
serum sodium concentration is unlikely to decrease on withdrawal of the IMP, the 
treatment may be completed before the treatment duration reaches 30 days. 
If hyponatremia recurs after treatment with the IMP has been completed (except for 
treatment discontinuations as specified in Section 3.8.3.1) and the investigator or 
subinvestigator judges that readministration with the IMP is necessary, treatment may be 
resumed within 30 days after the initial IMP administration (for the readministration 
procedure, see Appendix 3). 


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[Rationale for the treatment duration] 
The maximum duration of treatment is set as 30 days, which is the same as that used in 
the phase 3 trials previously conducted in the US and EU, and is sufficient to evaluate the 
effect of tolvaptan on correction and maintenance of serum sodium concentration. 
Treatments for hyponatremia may become unnecessary after IMP administration is 
started due to improvement of the etiology of SIADH. To avoid the chronic 
administration of tolvaptan, the treatment duration is not uniformly specified in this trial, 
and the completion of IMP treatment is allowed at any time, when treatment with 
tolvaptan is judged to be unnecessary based on an individual subject’s condition at 
discretion of the investigator or subinvestigator. 
3.2.5 
Hospitalization 
 
1) Hospitalization required from 2 days before start of IMP administration 
The subject is required to be hospitalized before supper 2 days before start of IMP 
administration. 
On the day after the maintenance dose is determined, the investigator or 
subinvestigator may determine whether the subject meets the following criterion for 
switching to outpatient treatment. By meeting the criterion, the subject may be 
transferred to outpatient treatment from the following day of assessment and onward. 
Criterion for switching to outpatient treatment 
 The predose serum sodium concentration has not increased by >2 mEq/L, as 
compared with predose on the previous day. 
If the criterion for switching to outpatient treatment is not met on the day after the 
maintenance dose is determined, the serum sodium concentration will be measured 
again at predose on the following day to determine the switching. The subject may be 
moved to outpatient treatment on or after the day the criterion for switching to 
outpatient treatment is met. 
The investigator or subinvestigator will record the dates the subject is admitted to and 
discharged from the trial site in the source document and case report form (CRF). 
2) Re-hospitalization after switching to outpatient treatment 
A subject who has been switched to outpatient treatment will be rehospitalized by the 
day before the day dose escalation or readministration is started, if either of the 
following criteria is met: 
 A new increased maintenance dose beyond the fixed maintenance dose, becomes 
necessary due to the lack of efficacy or other reasons; OR 


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 Readministration is started after completion of IMP treatment. 
The timing of discharge from the trial site after readmission will be decided as 
specified in 1) Hospitalization required from 2 days before start of IMP 
administration. 
The investigator or subinvestigator will record the dates the subject is admitted to and 
discharged from the trial site in the source document and CRF. 
3.3 
Trial Population 
 
3.3.1 
Number of Subjects and Description of Population 
 
In this trial, male and female Japanese patients with hyponatremia secondary to SIADH, 
aged from 20 to 85, inclusive at the time of consent are eligible. The trial population must 
include 16 subjects who are evaluable for the primary endpoint, the percentage of 
subjects with normalized serum sodium concentration (ie, subjects whose predose serum 
sodium concentration centrally measured on Day 1 is <135 mEq/L). Subject enrollment 
will be continued until a total of 16 evaluable subjects have been obtained. 
At least 50% (8/16) of the above subjects should comprise subjects with serum sodium 
concentration of <130 mEq/L at predose on Day 1 of the treatment period. In addition, 
the number of subjects with SIADH due to ectopic antidiuretic hormone-producing 
tumors and the number of subjects with SIADH due to other causes should not be notably 
different. 
3.3.2 
Subject Identification Number 
 
A subject identification number (site number [3 digits] + S + a serial number within the 
site [5 digits]) will be assigned to each subject. The site number (3 digits) is designated 
by the sponsor, while the serial number within each site (5 digits) is assigned from 00001, 
in the order of obtainment of informed consent within that site. The trial site will prepare 
a list of subjects who have provided informed consent and their subject identification 
numbers, and retain the list. 
3.4 
Eligibility Criteria 
 
3.4.1 
Informed Consent 
 
Informed consent will be freely obtained from all subjects. By signing the informed 
consent form (ICF), consent of the subject will be recorded in document form. Both the 
written information for the subjects and the ICF will be approved by the same 
Institutional Review Board (IRB) that approves this protocol. 


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The written information for the subjects and ICF will comply with the International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline10 and local 
regulatory requirements. 
Before obtaining informed consent, the investigator or subinvestigator may discuss with 
potential subjects regarding the possibility of participation or enrollment in the trial. 
However, informed consent must be obtained and documented prior to initiation of any 
procedures that are performed solely for the purpose of determining eligibility for 
research, including withdrawal from current medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care. 
Once appropriate essential information has been provided and fully explained in layman's 
language to the subject by the investigator or subinvestigator, the IRB-approved written 
ICF will be signed and dated by both the subject and the person obtaining consent 
(investigator or subinvestigator). The ICF will also be signed and dated by a clinical trial 
associate, in cases where they also provide a supplemental explanation. The subject will 
receive the written information for subjects and a copy of the signed ICF; the original 
shall be kept on file by the investigator or subinvestigator. 
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol result in additional information that needs to be provided to the subjects. 
3.4.2 
Inclusion Criteria 
 
The investigator or subinvestigator will confirm that subjects meet all of the inclusion 
criteria listed in Table 3.4.2-1. Confirmations will be made for criteria 1, 2, 4, and 5 at the 
screening examination, and for criterion 3 during the pretreatment observation period (the 
day before start of IMP administration) and predose on Day 1. Serum sodium 
concentrations measured at each trial site will be used in the eligibility assessment. 


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Table 3.4.2-1 
Inclusion Criteria 
1. 
Subjects with a definite diagnosis of SIADH in reference to “Diagnostic and Treatment Manual of 
the Hypersecretion of Vasopressin (SIADH), Revised in 2011” (Appendix 1) 
2. 
Subjects who have been on fluid restriction (total daily fluid intake of ≤20 mL/kg body weight) for 
at least 7 consecutive days at the time of informed consent and who are showing no improvement  
of hyponatremia (serum sodium concentration of <135 mEq/L) at the time of the screening 
examination. 
3. 
Subjects who have been on fluid restriction from the time of the screening examination until the 
pretreatment observation (day before start of IMP administration) but whose serum sodium 
concentration at both the pretreatment observation and at predose on Day 1 of the treatment period 
is <135 mEq/L and increased by <5 mEq/L compared with that at the screening examination 
4. 
Male and female Japanese subjects age 20 to 85 years, inclusive, at the time of informed consent 
5. 
Subjects from whom informed consent can be obtained before start of the trial 
 
When determining whether the subject satisfies criterion 1 in Table 3.4.2-1, the plasma 
AVP concentration measured at the screening examination will be used, as a rule. If the 
plasma AVP concentration was measured as part of routine medical practice prior to 
participation in the trial, that result may be used for the subject’s eligibility assessment 
without measuring the plasma AVP concentration at the screening examination (this only 
applies if the previous measurement was performed using a blood sample collected 
within 30 days prior to the scheduled start of IMP administration). 
3.4.3 
Exclusion Criteria 
 
Subjects who meet any of the exclusion criteria listed in Table 3.4.3-1 at the screening 
examination will be excluded from the trial. In addition, subjects who meet any of 
exclusion criteria 14, 22, 28, or 29 in Table 3.4.3-1 during the pretreatment observation 
period (the day before start of IMP administration) or predose on Day 1 will also be 
excluded. 
Serum sodium concentrations measured at each trial site will be used in the eligibility 
assessment. 
[Rationale for the inclusion criteria] 
Criteria 1 to 3 are set to appropriately evaluate the efficacy and safety of tolvaptan in the 
treatment of hyponatremia secondary to SIADH. 
The lower age limit in criterion 4 is set to enroll only adults with a sufficient capability to 
provide consent to participate in the trial. The upper age limit is set to reflect the 
considerations for the common development of some underlying diseases of SIADH at an 
older age as well as to ensure subject safety. 
Criterion 5 is set to ensure the ethical conduct of the trial. 


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Table 3.4.3-1 
Exclusion Criteria 
1 
Subjects who have transient hyponatremia induced by drug administration 
2 
Subjects with dehydration 
3 
Subjects with hyponatremia due to heart failure, ascites associated with hepatic cirrhosis, or 
nephrotic syndrome 
4 
Subjects with SIADH due to unknown etiology 
5 
Subjects with substantial sodium transudation due to renal sodium loss, diarrhea, or vomiting 
6 
Subjects who are unable to sense thirst or who have difficulty with fluid intake 
7 
Subjects who have impaired consciousness (coma or stupor) 
8 
Subjects who have AST (GOT) or ALT (GPT) exceeding 3 times the upper limit of normal at the 
screening examination 
9 
Subjects who have a history of myocardial infarction within 30 days prior to informed consent 
10 
Subjects who have a history of persistent ventricular tachycardia or ventricular fibrillation despite 
having an implantable cardioverter defibrillator within 30 days prior to informed consent 
11 
Subjects with decubitus angina, exertional angina induced by even mild exertion, or severe angina 
such as unstable angina 
12 
Subjects with a history of cerebrovascular disorder within 30 days prior to informed consent 
13 
Subjects with a severe psychiatric disorder 
14 
Subjects with systolic blood pressure of <90 mmHg at the time of the screening examination or at 
the pretreatment observation on the day before start of IMP administration 
15 
Subjects with a history of hypersensitivity or idiosyncratic reaction to benzazepine or benzazepine 
derivatives such as benazepril 
16 
Subjects with a history of drug abuse within 1 year prior to informed consent or with current  
alcohol dependence 
17 
Subjects  with  poorly  controlled  diabetes  mellitus,  defined  as  fasting  blood  glucose  level    of 
>300 mg/dL 
18 
Subjects with urinary tract obstruction 
19 
Subjects who have participated in any other clinical trial within 30 days prior to informed consent 
20 
Subjects who have participated in another clinical trial of tolvaptan or who have  previously 
received tolvaptan 
21 
Subjects who are in the terminal stage of the disease or in a moribund state with an expected 
survival of less than 3 months as judged by the investigator or subinvestigator 
22 
Subjects with serum sodium concentration of <120 mEq/L associated with neurologic impairment, 
including apathy, confusion, or seizures 
23 
Subjects with a progressive or episodic neurological disorder, including multiple sclerosis or with a 
history of multiple strokes 
24 
Subjects with acute or transient hyponatremia due to head trauma or postoperative condition 
25 
Subjects who are receiving intravenous infusion fluid at a keep-vein-open (KVO) volume (at the 
minimum fluid volume for preventing blood clots after the planned volume of fluid infusion) or 
higher 
26 
Subjects with hyponatremia due to an artifact in laboratory tests (eg, a high blood glucose level   of 
>300 mg/dL) 
27 
Subjects who are receiving arginine vasopressin (AVP) or an AVP analog for the treatment of the 
disease 
28 
Subjects who receive any other drugs for the treatment of hyponatremia, including demeclocycline, 
lithium carbonate, or urea within 7 days prior to start of IMP administration 
29 
Subjects who have concomitantly used hypertonic saline for correction of serum sodium 
concentration within 7 days prior to informed consent or who are likely to require intravenous 
hypertonic saline infusion for correction of symptomatic or asymptomatic severe hyponatremia 
during the trial period 
30 
Subjects with severe pulmonary hypertension: subjects whose disease state could be expected to 
worsen due to sudden changes in body fluid volume and blood pressure 


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Table 3.4.3-1 
Exclusion Criteria 
31 
Female subjects who are breast-feeding at the planned start of IMP administration or who are 
judged by the investigator or subinvestigator to be possibly pregnant based on the results of the 
pregnancy test at the screening examination. 
32 
Male subjects or female subjects of childbearing potential who are sexually active and who do not 
agree to practice birth control as specified or to remain abstinent during the trial and until 30 days 
after final IMP administration 
 
Subjects who have met any of the exclusion criteria and were thereby excluded from the 
trial may undergo the screening examination again, if there are changes in the criterion 
(criteria) that the subjects met. When the screening examination is repeated, the 
investigator or subinvestigator should obtain a new informed consent from the subject 
and assign a new subject identification number to that subject, prior to performing the 
second screening examination. 
Nonchildbearing potential is defined as male and female subjects who are surgically 
sterile (ie, male subjects who have undergone bilateral orchidectomy and female subjects 
who have undergone bilateral oophorectomy and/or hysterectomy). 
Subjects must agree to the restriction of drug use as specified in Section 4. 
 
 
3.5 
Endpoints 
 
3.5.1 
Efficacy 
 
3.5.1.1 
Primary Endpoint 
 Percentage of subjects with normalized serum sodium concentration on the day after 
final IMP administration 
[Rationale for the exclusion criteria] 
Criteria 1, 20, and 24 to 27 are set considering the effects on the efficacy or safety 
evaluation. 
Criteria 2 to 5 are set according to “Diagnosis and Treatment Manual of Hypersecretion 
of Vasopressin (SIADH), Revised in 2011” (Appendix 1), to appropriately evaluate the 
efficacy and safety of tolvaptan in the treatment of hyponatremia secondary to SIADH. 
Criteria 6 to 19, 21 to 23, and 30 are set considering the effects on the safety evaluation. 
Criteria 28 and 29 are set considering the effects on the efficacy evaluation. 
Criteria 31 and 32 are set because tolvaptan has been shown to be teratogenic and 
embryo-fetal lethal (in rabbits), and excreted into milk (in rats). 


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3.5.1.2 
Secondary Endpoints 
 Change in serum sodium concentration 
 Time course of serum sodium concentration 
 Changes in clinical symptoms associated with hyponatremia 
 
3.5.2 
Pharmacodynamics 
 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Serum osmolality 
 Urine osmolality 
 Daily urinary sodium excretion 
 Plasma AVP concentration 
 
3.5.3 
Pharmacokinetics 
 
The plasma concentrations of tolvaptan and its metabolites (DM-4103 and DM-4107) 
3.5.4 
Safety 
 
 AEs 
 Clinical laboratory tests 
 Body weight and vital signs 
 12-Lead electrocardiography 
 Liver function tests 
 
3.6 
Measures to Minimize/Avoid Bias 
 
This trial is an uncontrolled trial. 
3.7 
Trial Procedures 
 
The assessment schedule is presented in Table 3.7-1. 


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Table 3.7-1 
Schedule of Assessments (1/2) 
Screening Period 
Pretreatment 
Observation Period 
Treatment Period 
Day −14 
to Day −2 
Day −2 
Day −1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Informed Consent 
● 
Hospitalizatio a,b 
n 
● 
Subject Background 
● 
Eligibility Assessment 
● 
● 
c 
● 
d 
IMP Administration 
Confirmation of Concomitant Drugs and Therapies 
● 
● 
● 
● 
● 
● 
● 
● 
Clinical Symptoms Associated with Hyponatremia 
● 
● 
● 
● 
● 
Fluid intake restriction (≤20 mL/kg/day) 
Fluid intake restrictio e 
n 
IMP Compliance 
● 
● 
● 
● 
● 
● 
Day −14 
to Day −2 
Day −2 
Day −1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Predose Postdose Predos f 
e 
Predos f 
e 
Predos f 
e 
Predos f 
e 
Serum Sodium Concentrationg 
● 
● 
● 
● 
● 
● 
● 
● 
Body Weight 
● 
● 
● 
● 
● 
● 
● 
Daily Urine Volume, Fluid Intake, and Fluid 
Balance, and Urinary Sodium Ex 
h 
cretion 
● 
i 
Urine Osmolality 
● 
Serum Osmolality 
● 
● 
● 
● 
● 
● 
Plasma Drug Concentration (Blood Sampling) 
Laboratory Tests (Blood/Urine Sampling) 
● 
● 
● 
Liver Function Test (Blood Sampling j 
) 
● 
● 
● 
● 
Vital Signk 
● 
● 
● 
● 
● 
● 
● 
12-Lead Electrocardiography 
● 
● 
Serum Cortisol 
● 


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Table 3.7-1 
Schedule of Assessments (1/2) 
Screening Period 
Pretreatment 
Observation Period 
Treatment Period 
Day −14 
to Day −2 
Day −2 
Day −1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Plasma AVP Concentration 
l 
● 
● 
Pregnancy Testm 
● 
Adverse Events 


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Table 3.7-1 
Schedule of Assessments (2/2) 
Treatment Period 
Day After Final 
IMP 
Administration 
Follow-up Exam After the 
End-of-Treatment 
Day 7 
(±1 da   n 
y) 
Day 14 
(±1 da   o 
y) 
Day 21 
(±1 da   o 
y) 
Until the 
At the Time 
When 
At 
Measurement 
Follow-up 
Maintenance 
of 
Determining Withdrawal 
of serum 
examination 
Dose 
Maintenance Possibility of 
sodium 
Determination 
Dose 
Switching to 
concentration 
Determined 
Outpatient 
Treatment 
3 to 5 days 
7 to 10 days 
after 
after 
completion 
completion 
Informed Consent 
Hospitalization 
Subject Background 
Eligibility Assessment 
IMP Administration 
p 
p 
p 
Confirmation of Concomitant 
Drugs and Therapies 
● 
● 
● 
● 
● 
● 
Clinical Symptoms Associated 
with Hyponatremia 
● 
● 
● 
● 
● 
● 
● 
● 
Fluid intake restriction 
(≤20 mL/kg/day) 
Fluid intake restric 
e 
tion 
IMP Compliance 
● 
● 
● 
● 
● 
Serum Sodium Concentratio q 
n 
● 
● 
● 
r 
● 
● 
● 
● 
● 
● 
Body Weight 
● 
● 
● 
● 
● 
● 
Daily Urine Volume, Fluid 
Intake, and Fluid Balance, and 
Urinary Sodium Excretionh 
● 
Urine Osmolalit i y 
● 
Serum Osmolalit q 
y 
● 
● 
● 
● 
● 
● 
Plasma Drug Concentration 
(Blood Sampling q 
) 
● 
● 
● 


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a 
Hospitalization: Required from before supper 2 days prior to start of IMP administration. Possibility of switching to outpatient treatment will be determined 
for each subject on the day after the maintenance dose is determined as specified in Section 3.2.5. 
bHospitalization: As specified in Section 3.2.5, subjects who have switched to the outpatient treatment will be re-hospitalized if it becomes necessary to 
increase their dose of the IMP from the determined maintenance dose due to lack of efficacy or other reasons. Subjects will also be re-hospitalized if 
treatment is to be resumed after completion of IMP treatment. 
c 
Eligibility assessment will be performed before IMP administration on Day 1 of the treatment period. 
dIMP administration: 
IMP administration will be performed once daily after breakfast from Day 1 of the treatment period. The timing for the end of treatment will be 
individually determined for each subject as specified in Section 3.2.4. The maximum treatment duration will be 30 days. 
e 
From Day 2 to the completion of the examination on the day after the final IMP administration: Fluid intake from immediately before IMP administration on 
Day 1 to immediately before IMP administration on Day 2 will be the upper limit of the daily fluid intake. However, if thirst or dehydration, and other 
unfavorable symptoms develop, the subject should be instructed to take more fluids, irrespective of the upper limit, to ensure the safety of the subject. 
Table 3.7-1 
Schedule of Assessments (2/2) 
Treatment Period 
Day After Final 
IMP 
Administration 
Follow-up Exam After the 
End-of-Treatment 
Day 7 
(±1 da   n 
y) 
Day 14 
(±1 da   o 
y) 
Day 21 
(±1 da   o 
y) 
Until the 
At the Time 
When 
At 
Measurement 
Follow-up 
Maintenance 
of 
Determining Withdrawal 
of serum 
examination 
Dose 
Maintenance Possibility of 
sodium 
Determination 
Dose 
Switching to 
concentration 
Determined 
Outpatient 
Treatment 
3 to 5 days 
7 to 10 days 
after 
after 
completion 
completion 
Laboratory Tests (Blood/Urine 
Sampling q 
) 
● 
● 
● 
● 
● 
● 
Liver Function Tests (Blood 
Sampling q 
) 
● 
● 
● 
● 
● 
● 
Vital Sign 
● 
● 
● 
● 
● 
● 
12-Lead Electrocardiography 
● 
● 
● 
● 
Serum Cortisol 
Plasma AVP concentrationq 
● 
● 
● 
● 
● 
● 
Pregnancy Test 
● 
Adverse Events 


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f 
On Days 2 through 5 of the treatment period, predose laboratory tests and examinations will be performed at 21 to 24 hours after IMP administration on the 
previous day. 
g 
Serum sodium concentration 
 
Pretreatment observation period (day before start of IMP administration): Blood sampling will be performed at approximately 24 hours before the 
scheduled initial IMP administration. 
 
Day 1 of the treatment period: Blood sampling will be performed at predose and at 4 to 6 hours and 8 to 12 hours postdose. 
 
Days 2 to 5 of the treatment period: Until the maintenance dose is determined, blood sampling will also be performed at 4 to 6 hours postdose on days on 
which the dose is increased. 
hDaily urine volume, fluid intake, and fluid balance and urinary sodium excretion 
 
Screening period (Day −14 to −2): Only urinary sodium excretion will be measured. 
 
Pretreatment observation period (day before start of IMP administration): Cumulative 24-hour urine volume and fluid intake volume will be measured 
from after complete urination after breakfast until after complete urination immediately before IMP administration on Day 1 of the treatment period. 
 
Treatment period: Measurement of cumulative urine volume and fluid intake will start after complete urination after breakfast on Day 1. The time until 
after complete urination immediately before IMP administration on the following day will be defined as one collection period, and the measurement of 
daily urine volume and fluid intake volume for each collection period will continue until the maintenance dose is determined. 
iUrine osmolality: 
In the pretreatment observation period and treatment period, measurement will be performed using urine samples from the cumulatively collected urine. 
jLiver function tests (blood sampling): AST (GOT), ALT (GPT), and serum total bilirubin will be measured. 
k 
Vital signs: Blood pressure, pulse rate, and body temperature will be measured. 
lPlasma AVP concentration: 
For determining whether the subject satisfies the inclusion criteria, in principle, plasma AVP concentration measured at the time of screening examination 
will be used. However, if plasma AVP concentration has already been measured at a regular visit prior to the subject’s participation in the trial, that result 
may be used for assessment without measuring plasma AVP concentration at the screening examination (this only applies if the previous measurement was 
performed using a blood sample collected within 30 days prior to the scheduled start of IMP administration). 
m 
Pregnancy test: Performed in only females of childbearing potential. 
nDay 7 of the treatment period: 
If subjects who have switched to outpatient treatment have difficulty coming to the trial site on the day of the scheduled visit for some reason, a margin of 
+1 day is allowed. 
oDays 14 and 21 of the treatment period: 
If subjects who have switched to outpatient treatment have difficulty coming to the trial site on the day of the scheduled visit for some reason, a margin of 
±1 day is allowed. 


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pIMP administration: 
On Days 7, 14, and 21, if subjects visit the trial site for examination, IMP administration is to be performed in the morning after blood sampling. 
qSerum sodium concentration, serum osmolality, plasma drug concentrations (blood sampling), laboratory tests (blood/urine sampling), liver function test 
(blood sampling), and plasma AVP concentration: 
For measurement on Day 21 of the treatment period and on the day after final IMP administration, blood sampling will be performed at 22 to 24 hours after 
IMP administration on the previous day. For other measurement timepoints, blood sampling will be performed at 21 to 24 hours after IMP administration 
on the previous day. If it is difficult to perform blood sampling at 22 to 24 hours after IMP administration on the previous day for subjects who have 
switched to outpatient treatment, blood sampling for days other than the day after final IMP administration can be performed anytime in the morning before 
IMP administration. 
 
Serum sodium concentration: 
Days 7, 14, and 21 of the treatment period, the day after final IMP administration, and 3 to 5 days after completion of treatment 
 
Serum Osmolality: 
Days 7, 14, and 21 of the treatment period and the day after final IMP administration 
 
Plasma drug concentrations (blood sampling): 
Day 21 of the treatment period and the day after final IMP administration 
 
Laboratory tests (blood/urine sampling): 
Days 7, 14, and 21 of the treatment period and the day after final IMP administration 
 
Liver function tests (blood sampling): 
Days 7, 14, and 21 of the treatment period and the day after final IMP administration 
 
Plasma AVP concentration: 
Days 7, 14, and 21 of the treatment period and the day after final IMP administration 
r 
Serum sodium concentration: Blood sampling will be performed at predose every day until the maintenance dose will be determined. Blood sampling will 
also be performed at 4 to 6 hours postdose on days which the dose is increased. 


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3.7.1 
Schedule of Assessments 
 
3.7.1.1 
Screening Period (14 to 2 Days Before Start of IMP 
Administration) 
After informed consent has been obtained, the investigator or subinvestigator will assign 
a subject identification number to the subject according to Section 3.3.2, and record the 
date of acquisition of informed consent and the assigned subject identification number in 
the source document and CRF. 
The investigator or subinvestigator will perform the following examinations and 
investigations, confirm that the subject meets all of the inclusion criteria and none of the 
exclusion criteria, and then record the results of the confirmation in the source document 
and CRF. 
1) Assessment of subject background 
The investigator or subinvestigator will investigate the subject background for the 
following items, and record the results in the source document and CRF. 
 Birth date 
 Gender 
 Height 
 Race 
 Ethnicity 
 Complications 
 Medical history 
 Etiology of SIADH 
 Date of diagnosis of SIADH 
(Date on which the latest diagnosis of SIADH was made [or the date on which 
hyponatremia requiring treatment was diagnosed]) 
 Diagnoses and treatments of SIADH prior to participation in the trial 
(Perform an investigation, as specified in 2) Investigation of diagnoses and 
treatments prior to participation in the trial.) 
2) Investigation of diagnoses and treatments prior to participation in the trial 
The investigator or subinvestigator will investigate the following items, and record 
the results in the source document and CRF. 
 Serum sodium concentrations before participation in the trial 
The investigator or subinvestigator will identify the following serum sodium 
concentrations measured within 30 days before the day of informed consent 
acquisition, and record each value, along with the date on which the value was 
measured. 


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 The highest serum sodium concentration observed after SIADH was 
diagnosed 
 The lowest serum sodium concentration observed after SIADH was diagnosed 
 The serum sodium concentration just after fluid intake restriction was started 
 Clinical symptoms associated with hyponatremia before participation in the trial 
The investigator or subinvestigator will identify the following clinical symptoms 
observed within 30 days before the day of informed consent acquisition, and record 
the presence/absence of each symptom and its severity, along with the date on 
which each symptom was observed. 
 Anorexia associated with hyponatremia 
 Vomiting associated with hyponatremia 
 Headache associated with hyponatremia 
 Consciousness disturbed associated with hyponatremia 
 Malaise associated with hyponatremia 
 Other symptoms associated with hyponatremia, if any 
 Treatments of hyponatremia secondary to SIADH before participation in the trial 
The investigator or subinvestigator will identify the following treatments given 
within 30 days before the day of informed consent acquisition, and record the dates 
on which the treatment was started and completed. 
 Fluid intake restriction 
 Treatments other than fluid intake restriction, if any 
3) Examinations and assessments 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 Serum sodium concentration 
 Body weight 
 Urine osmolality 
 Serum osmolality 
 Laboratory tests (blood/urine sampling) 
 Liver function tests (blood sampling) 
 Vital signs (blood pressure, pulse rate, body temperature) 
 12-Lead electrocardiography 
 Serum cortisol concentration 
 Plasma AVP concentration 
 Urine sodium concentration 
 Pregnancy test (human chorionic gonadotropin [hCG]) for female subjects of 
childbearing potential 


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If the plasma AVP concentration was measured as part of routine medical practice prior 
to participation in the trial, that result may be used for the subject’s eligibility assessment, 
without measuring the plasma AVP concentration at the screening examination (this only 
applies if the previous measurement was performed using a blood sample collected 
within 30 days prior to the scheduled start of IMP administration). 
3.7.1.2 
Screening Period (2 Days Before Start of IMP Administration) 
The investigator or subinvestigator will admit the subject to the trial site before supper to 
perform the following investigations. 
 Confirmation of concomitant drugs and therapies 
 AEs 
 
3.7.1.3 
Pretreatment Observation Period (Day Before Start of IMP 
Administration) 
The investigator or subinvestigator will perform the following examinations and 
investigations, confirm that the subject meets all of the inclusion criteria and none of the 
exclusion criteria, and then record the results of confirmation on the source document and 
CRF. 
1) Approximately 24 hours before the scheduled time of the initial IMP 
administration 
The investigator or subinvestigator will perform the following examinations, and then 
offer breakfast to the subject. 
 Serum sodium concentration 
Subjects are required to urinate completely immediately after breakfast, and then the 
investigator or subinvestigator will start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urinary sodium excretion 
 Urine osmolality 
2) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 Body weight 
 Vital signs (blood pressure, pulse rate, body temperature) 


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 12-Lead electrocardiography 
 AEs 
 
3.7.1.4 
Day 1 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. Fluid intake 
must not be restricted within 24 hours from immediately after the initial IMP 
administration on Day 1 of treatment period. 
1) Before IMP administration 
The investigator or subinvestigator will perform the following examinations, and then 
offer breakfast to the subject. 
 Serum sodium concentration 
 Body weight 
 Serum osmolality 
 Laboratory tests (blood/urine sampling) 
 Liver function tests (blood sampling) 
 Vital signs (blood pressure, pulse rate, body temperature) 
 Plasma AVP concentration 
Subjects are required to urinate completely immediately after breakfast, and then the 
investigator or subinvestigator will start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urinary sodium excretion 
 Urine osmolality 
2) IMP administration 
The investigator or subinvestigator will confirm that the subject meets all of the 
inclusion criteria and none of the exclusion criteria, and then administer one 7.5 mg 
tolvaptan tablet with water. After administration, the investigator or subinvestigator 
will observe the change in serum sodium concentration, and if the following criterion 
is met, discontinue treatment with the IMP as specified in Section 3.8.3.1, followed 
by performance of the examination at withdrawal according to Section 3.7.1.19. 
 Serum sodium concentration increased by ≥12 mEq/L from predose, within 
24 hours after the IMP administration. 


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3) 4 to 6 hours after IMP administration 
 Serum sodium concentration 
4) 8 to 12 hours after IMP administration 
 Serum sodium concentration 
5) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 IMP compliance 
 AEs 
 
3.7.1.5 
Day 2 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. Fluid intake 
must not be restricted within 24 hours after IMP administration on Day 1 of the treatment 
period. On or after Day 2 of treatment period, if the serum sodium concentration has 
increased by ≥12 mEq/L within 24 hours from immediately before IMP administration, 
treatment with the IMP should be discontinued as specified in Section 3.8.3.1, and the 
examination at withdrawal will be performed according to Section 3.7.1.19. 
1) Before IMP administration (21 to 24 hours after IMP administration on the day 
before) 
The investigator or subinvestigator will perform the following examinations, and then 
offer breakfast to the subject. 
 Serum sodium concentration 
 Body weight 
 Serum osmolality 
 Vital signs (blood pressure, pulse rate, body temperature) 
Subjects are required to urinate completely immediately after breakfast, and the 
investigator or subinvestigator will start urine collection and fluid intake 
measurement to assess the following items. If the maintenance dose has already been 
determined, tolvaptan tablets should be administered at the maintenance dose with 
water after breakfast, without performing the measurements below. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urinary sodium excretion 
 Urine osmolality 


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2) IMP administration 
The investigator or subinvestigator will select the dose of the IMP based on the 
change in serum sodium concentration from predose of the IMP administration on the 
day before as specified in Section 3.2.2, and administer tolvaptan tablets to subjects at 
that dose with water, unless the maintenance dose has already been determined. 
The investigator or subinvestigator will confirm the fluid intake within 24 hours after 
the IMP administration on Day 1 of treatment period, and instruct the subject to 
adhere to Section 4.2 on or after Day 2 of treatment period. 
3) 4 to 6 hours after IMP administration 
If the maintenance dose is not determined on Day 2 of treatment period and the dose 
is increased on that day according to Section 3.2.2, the investigator or subinvestigator 
will perform the following examinations 4 to 6 hours after IMP administration. 
 Serum sodium concentration 
4) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 IMP compliance 
 AEs 
5) When the maintenance dose is determined 
If the maintenance dose is to be determined on Day 2 of treatment period, the 
investigator or subinvestigator will perform the procedures as specified in 
Section 3.7.1.16. 
3.7.1.6 
Day 3 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before IMP administration (21 to 24 hours after IMP administration on the day 
before) 
The investigator or subinvestigator will perform the following examinations, and then 
offer breakfast to the subject. 
 Serum sodium concentration 
 Body weight 
 Serum osmolality 
 Liver function tests (blood sampling) 
 Vital signs (blood pressure, pulse rate, body temperature) 
Subjects are required to urinate completely immediately after breakfast, and the 
investigator or subinvestigator will start urine collection and fluid intake 
measurement to assess the following items. If the maintenance dose has been already 


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determined, tolvaptan tablets should be administered at the maintenance dose with 
water after breakfast, without performing the measurements below. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urinary sodium excretion 
 Urine osmolality 
2) IMP administration 
The investigator or subinvestigator will select the dose of the IMP based on the 
change in serum sodium concentration from predose of the IMP administration on the 
day before as specified in Section 3.2.2, and administer tolvaptan tablets to subjects at 
that dose with water, unless the maintenance dose has already been determined. 
In addition, the investigator or subinvestigator will instruct the subject to adhere to 
Section 4.2. 
3) 4 to 6 hours after IMP administration 
If the maintenance dose is not determined on Day 3 of treatment period and the dose 
is to be increased on the same day according to Section 3.2.2, the investigator or 
subinvestigator will perform the following examinations 4 to 6 hours after IMP 
administration. 
 Serum sodium concentration 
4) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 IMP compliance 
 AEs 
5) When the maintenance dose is determined 
If the maintenance dose is determined on Day 3 of treatment period, the investigator 
or subinvestigator will perform the procedures specified in Section 3.7.1.16. 
6) When determining possibility of switching to outpatient treatment 
When determining possibility of switching to outpatient treatment as specified in 
Section 3.2.5 is needed for subjects whose maintenance dose were determined on the 
day before, the investigator or subinvestigator is to perform the procedures as 
specified in Section 3.7.1.17. 


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3.7.1.7 
Day 4 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before IMP administration (21 to 24 hours after IMP administration on the day 
before) 
The investigator or subinvestigator will perform the following examinations, and then 
offer breakfast to the subject. 
 Serum sodium concentration 
 Body weight 
 Serum osmolality 
 Vital signs (blood pressure, pulse rate, body temperature) 
Subjects are required to urinate completely immediately after breakfast, and the 
investigator or subinvestigator will start urine collection and fluid intake 
measurement to assess the following items. If the maintenance dose has been already 
determined, tolvaptan tablets should be administered at the maintenance dose with 
water after breakfast, without performing the examinations below. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urinary sodium excretion 
 Urine osmolality 
2) IMP administration 
The investigator or subinvestigator will select the dose of the IMP based on the 
change in serum sodium concentration from predose of the IMP administration on the 
day before as specified in Section 3.2.2, and administer tolvaptan tablets to subjects at 
that dose with water, unless the maintenance dose has already been determined. 
In addition, the investigator or subinvestigator will instruct the subject to adhere to 
Section 4.2. 
3) 4 to 6 hours after IMP administration 
If the maintenance dose is not determined on Day 4 of treatment period and the dose 
is to be increased on the same day according to Section 3.2.2, the investigator or 
subinvestigator will perform the following examinations 4 to 6 hours after IMP 
administration. 
 Serum sodium concentration 


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4) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 IMP compliance 
 AEs 
5) When the maintenance dose is determined 
If the maintenance dose is to be determined on Day 4 of treatment period, the 
investigator or subinvestigator will perform the procedures specified in 
Section 3.7.1.16. 
6) When determining possibility of switching to outpatient treatment 
When determining possibility of switching to outpatient treatment as specified in 
Section 3.2.5 is needed for subjects whose maintenance dose were determined on the 
day before, the investigator or subinvestigator is to perform the procedures as 
specified in Section 3.7.1.17. 
3.7.1.8 
Day 5 of Treatment Period 
The investigator or subinvestigator will perform the following procedures. 
1) Before IMP administration (21 to 24 hours after IMP administration on the day 
before) 
The investigator or subinvestigator will perform the following examinations, and then 
offer breakfast to the subject. 
 Serum sodium concentration 
 Body weight 
 Serum osmolality 
 Laboratory tests (blood/urine sampling) 
 Liver function tests (blood sampling) 
 Vital signs (blood pressure, pulse rate, body temperature) 
Subjects are required to urinate completely immediately after breakfast, and the 
investigator or subinvestigator will start urine collection and fluid intake 
measurement to assess the following items. If the maintenance dose has been already 
determined, tolvaptan tablets should be administered at the maintenance dose with 
water after breakfast, without performing the examinations below. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urinary sodium excretion 
 Urine osmolality 


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2) IMP administration 
The investigator or subinvestigator will select the dose of the IMP based on the 
change in serum sodium concentration from predose of the IMP administration on the 
day before as specified in Section 3.2.2, and administer tolvaptan tablets to subjects at 
that dose with water, unless the maintenance dose has already been determined. 
In addition, the investigator or subinvestigator will instruct the subject to adhere to 
Section 4.2. 
3) 4 to 6 hours after IMP administration 
If the maintenance dose is not determined on Day 5 of treatment period and the dose 
is to be increased on the same day according to Section 3.2.2 on the same day, the 
investigator or subinvestigator will perform the following examinations 4 to 6 hours 
after IMP administration. 
 Serum sodium concentration 
4) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 IMP compliance 
 AEs 
5) When the maintenance dose is determined 
If the maintenance dose is to be determined on Day 5 of treatment period, the 
investigator or subinvestigator will perform the procedures specified in 
Section 3.7.1.16. 
6) When determining possibility of switching to outpatient treatment 
When determining possibility of switching to outpatient treatment as specified in 
Section 3.2.5 is needed for subjects whose maintenance dose were determined on the 
day before, the investigator or subinvestigator is to perform the procedures as 
specified in Section 3.7.1.17. 
3.7.1.9 
Day 6 of Treatment Period 
Subjects with an individual maintenance dose (including subjects who have already 
switched to outpatient treatment after determination of the maintenance dose) will receive 
tolvaptan tablets according to the individually determined maintenance dose with water 
after breakfast, and are not required to undergo the following examinations as described 
in items 1) and 2) on Day 6 of treatment period. 


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1) Procedures (if the maintenance dose has not been determined) 
Follow the procedures specified in Section 3.7.1.15. 
2) When the maintenance dose is determined 
If the maintenance dose is to be determined on Day 6 of treatment period, the 
investigator or subinvestigator will perform the procedures as specified in 
Section 3.7.1.16. 
3) When determining possibility of switching to outpatient treatment 
When determining possibility of switching to outpatient treatment as specified in 
Section 3.2.5 is needed for subjects whose maintenance dose were determined on the 
day before, the investigator or subinvestigator is to perform the procedures specified 
in Section 3.7.1.17. 
3.7.1.10 
Day 7 of Treatment Period 
The investigator or subinvestigator is to perform the following procedures on Day 7 of 
treatment period. If subjects who have switched to outpatient treatment have difficulty 
coming to the trial site on the day of the scheduled visit for some reason, a margin of +1 
day is allowed. 
If the investigator or subinvestigator judges to terminate treatment with the IMP 
according to the specifications in Section 3.2.4, the subjects should not receive the IMP 
administration on that day but undergo the examinations according to the procedures 
specified in Section 3.7.1.14. 
1) Before IMP administration (21 to 24 hours after the IMP administration on the 
day before) 
The investigator or subinvestigator will perform the following examinations. If the 
examinations that require a visit to the trial site cannot be performed within 21 to 24 
hours after the IMP administration on the day before, the examinations may be 
performed in the morning before IMP administration on Day 7. 
 Serum sodium concentration 
 Serum osmolality 
 Laboratory tests (blood/urine sampling) 
 Liver function tests (blood sampling) 
 Plasma AVP concentration 
Subjects are required to urinate completely immediately after breakfast, and the 
investigator or subinvestigator will start urine collection and fluid intake 
measurement to assess the following items. However, subjects with already 
determined maintenance doses (including subjects who have already switched to 


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outpatient treatment after determination of the maintenance dose) will receive 
tolvaptan tablets at the individually determined maintenance dose with water after 
breakfast, without undergoing the following measurements. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urinary sodium excretion 
 Urine osmolality 
2) IMP administration 
The investigator or subinvestigator will select the dose of the IMP based on the 
change in serum sodium concentration from predose of the IMP administration on the 
day before as specified in Section 3.2.2, and administer tolvaptan tablets to subjects at 
that dose with water, unless the maintenance dose has already been determined. 
In addition, the investigator or subinvestigator will instruct the subject to adhere to 
Section 4.2. 
3) 4 to 6 hours after administration 
If the maintenance dose is not determined on Day 7 of treatment period and the dose 
is to be increased on the same day according to Section 3.2.2, the investigator or 
subinvestigator will perform the following examinations 4 to 6 hours after IMP 
administration. 
 Serum sodium concentration 
4) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 Body weight 
 Vital signs (blood pressure, pulse rate, body temperature) 
 12-Lead electrocardiography 
 IMP compliance 
 AEs 
5) When the maintenance dose is determined 
If the maintenance dose is to be determined on Day 7 of treatment period, the 
investigator or subinvestigator will perform the procedures specified in 
Section 3.7.1.16. 


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6) When determining possibility of switching to outpatient treatment 
When determining possibility of switching to outpatient treatment as specified in 
Section 3.2.5 is needed for subjects whose maintenance dose were determined on the 
day before, the investigator or subinvestigator is to perform the procedures as 
specified in Section 3.7.1.17. 
3.7.1.11 
Days 8 to 10 of Treatment Period 
Subjects with an individual maintenance dose (including subjects who have already 
switched to outpatient treatment after determination of the maintenance dose) will receive 
tolvaptan tablets at the individually determined maintenance dose with water after 
breakfast, and are not required to undergo the following examinations as described in 
items 1) and 2) on Days 8 to 10 of treatment period. 
1) Procedures (if the maintenance dose has not been determined) 
Follow the procedures specified in Section 3.7.1.15. 
2) When the maintenance dose is determined 
If the maintenance dose is to be determined on Days 8 to 10 of treatment period, the 
investigator or subinvestigator will perform the procedures specified in 
Section 3.7.1.16. 
 
3) When determining possibility of switching to outpatient treatment 
When determining possibility of switching to outpatient treatment as specified in 
Section 3.2.5 is needed for subjects whose maintenance dose were determined on the 
day before, the investigator or subinvestigator is to perform the procedures as 
specified in Section 3.7.1.17. 
3.7.1.12 
Day 14 of Treatment Period 
The investigator or subinvestigator is to perform the following procedures on Day 14 of 
treatment period. If subjects who have switched to outpatient treatment have difficulty 
coming to the trial site on the day of the scheduled visit for some reason, a margin of ±1 
day is allowed. 
If the investigator or subinvestigator judges to terminate treatment with the IMP 
according to the specification in Section 3.2.4, the subjects should not receive the IMP 
administration on that day but undergo the examinations according to the procedures 
specified in Section 3.7.1.14. 


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1) Before IMP administration (21 to 24 hours after the IMP administration on the 
day before) 
The investigator or subinvestigator will perform the following examinations. If the 
examinations that require a visit to the trial site cannot be performed within 21 to 24 
hours after the IMP administration on the day before, the examinations may be 
performed in the morning before IMP administration on Day 14. 
 Serum sodium concentration 
 Serum osmolality 
 Laboratory tests (blood/urine sampling) 
 Liver function tests (blood sampling) 
 Plasma AVP concentration 
2) IMP administration 
Subjects will take tolvaptan tablets with water. In addition, the investigator or 
subinvestigator will instruct the subject to adhere to Section 4.2. 
3) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 Body weight 
 Vital signs (blood pressure, pulse rate, body temperature) 
 IMP compliance 
 AEs 
 
3.7.1.13 
Day 21 of Treatment Period 
The investigator or subinvestigator is to perform the following procedures on Day 21 of 
treatment period. If subjects who have switched to outpatient treatment have difficulty 
coming to the trial site on the day of the scheduled visit for some reason, a margin of ±1 
day is allowed. 
If the investigator or subinvestigator judges to terminate treatment with the IMP 
according to the specification in Section 3.2.4, the subjects should not receive the IMP 
administration on that day but undergo the examinations according to the procedures 
specified in Section 3.7.1.14. 
1) Before IMP administration (22 to 24 hours after IMP administration on the day 
before) 
The investigator or subinvestigator will perform the following examinations. If the 
examinations that require a visit to the trial site cannot be performed within 22 to 24 


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hours after the IMP administration on the day before, the examinations may be 
performed in the morning before IMP administration on Day 21. 
 Serum sodium concentration 
 Serum osmolality 
 Plasma drug concentration (blood sampling) 
 Laboratory tests (blood/urine sampling) 
 Liver function tests (blood sampling) 
 Plasma AVP concentration 
2) IMP administration 
Subjects will take tolvaptan tablets with water. In addition, the investigator or 
subinvestigator will instruct the subject to adhere to Section 4.2. 
3) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 Body weight 
 Vital signs (blood pressure, pulse rate, body temperature) 
 IMP compliance 
 AEs 
 
3.7.1.14 
Day After the Final IMP Administration 
On the day after the final IMP administration (the day following Day 30, or the day after 
the investigator or subinvestigator has decided to complete treatment with the IMP as 
specified in Section 3.2.4), the investigator or subinvestigator will perform the following 
procedures. 
If the investigator or subinvestigator makes a judgement to discontinue treatment with the 
IMP according to Section 3.8.3.1, the procedures as specified in Section 3.7.1.19 should 
be performed rather than the specifications as below. 
1) 22 to 24 hours after the final IMP administration 
The investigator or subinvestigator will perform the following examinations. If the 
examinations that require a visit to the trial site cannot be performed within 22 to 24 
hours after the IMP administration on the day before, the examinations may be 
performed on the morning of the day after the final IMP administration. 
 Serum sodium concentration 
 Serum osmolality 
 Plasma drug concentration (blood sampling) 


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 Laboratory tests (blood/urine sampling) 
 Liver function tests (blood sampling) 
 Plasma AVP concentration 
2) At a feasible time 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 Body weight 
 Vital signs (blood pressure, pulse rate, body temperature) 
 12-Lead electrocardiography 
 IMP compliance 
 AEs 
Subjects are to visit the trial site 3 to 5 days and 7 to 10 days after the final IMP 
administration (the completion of treatment) to undergo the examinations specified in 
Section 3.7.1.20. Even if treatment with the IMP is terminated before the duration of 
treatment reached 30 days, the examinations specified in Section 3.7.1.20 should be 
performed regardless of whether or not treatment maybe resumed. 
3.7.1.15 
Procedures to Be Performed Until the Maintenance Dose Is 
Determined 
The investigator or subinvestigator will perform the following procedures until the 
maintenance dose is determined (see Section 3.2.1 and Section 3.2.3), except for 
scheduled assessment days (Days 1 to 5, 7, 14, and 21), on which the specified 
procedures for each day should be performed. 
1) Before IMP administration (21 to 24 hours after the IMP administration on the 
day before) 
The investigator or subinvestigator will perform the following examinations, and then 
offer breakfast to the subject. 
 Serum sodium concentration 
Subjects are required to urinate completely immediately after breakfast, and the 
investigator or subinvestigator will start urine collection and fluid intake 
measurement to assess the following items. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Urinary sodium excretion 
 Urine osmolality 


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2) IMP administration 
The investigator or subinvestigator will select the dose of the IMP based on the 
change in serum sodium concentration from predose of the IMP administration on the 
day before as specified in Section 3.2.2, and administer tolvaptan tablets to subjects at 
that dose with water. 
The investigator or subinvestigator will record the date that the dose increase is 
assessed, along with the reasons if the dose is not increased in the source document 
and CRF. 
If the investigator or subinvestigator judges to reduce the dose of the IMP due to any 
tolerability problem (eg, the occurrence or deterioration of AEs), the dose should be 
down-titrated (to the next lower dose level than that on the previous day). If the 
tolerability problem continues after dose reduction, the dose may be further reduced. 
The dose at the time that the investigator or subinvestigator judges to be tolerable will 
be determined as the maintenance dose. 
3) 4 to 6 hours after IMP administration 
If the dose of the IMP is increased according to Section 3.2.2, the investigator or 
subinvestigator will perform the following examinations 4 to 6 hours after IMP 
administration. 
 Serum sodium concentration 
 
3.7.1.16 
When the Maintenance Dose of the IMP Is Determined 
On the day the maintenance dose of the IMP is determined according to Section 3.2.3, the 
investigator or subinvestigator will perform the following investigation. If the 
investigation has already been performed on the same day, it does not need to be repeated 
after the maintenance dose is determined. 
 Clinical symptoms associated with hyponatremia 
The investigator or subinvestigator will record the maintenance dose, the date the 
maintenance dose is determined, and the reasons for the determination in the source 
document and CRF. 
If dose adjustment is required after the maintenance dose has been determined, the 
investigator or subinvestigator will record the date on which the dose adjustment is made, 
along with the reason for the decision in the source document and CRF. 


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3.7.1.17 
When Switching to Outpatient Treatment 
The investigator or subinvestigator will make a judgement for switching the trial 
treatment to outpatient treatment according to the following procedures on the day after 
the maintenance dose is determined. If the examination has already been performed on 
the same day, it does not need to be repeated for the judgment regarding switching to 
outpatient treatment. 
1) Before IMP administration (21 to 24 hours after the IMP administration on the 
day before) 
 Serum sodium concentration 
2) Judgement for switching subjects to outpatient treatment 
The investigator or subinvestigator will make a judgement for switching to outpatient 
treatment according to the criterion for switching to outpatient treatment as specified 
in Section 3.2.5. If the criterion for switching to outpatient treatment is met, the 
subject may be discharged from the trial site on or after the day the judgement is 
made. 
Criterion for switching to outpatient treatment 
 The predose serum sodium concentration on the day of judgement has not 
increased by >2 mEq/L compared with predose on the day before. 
If switching to outpatient treatment is not allowed because the criterion for switching 
to outpatient treatment is not met as specified in Section 3.2.5, the predose serum 
sodium concentration on the following day will be evaluated for a reassessment of the 
possibility of switching to outpatient treatment. 
 
3.7.1.18 
Change in the Maintenance Dose of the IMP 
If the dose of the IMP has to be increased beyond the maintenance dose after it has been 
determined due to lack of efficacy or other reasons, and a new maintenance dose must be 
determined, the investigator or subinvestigator should perform the following procedures 
in an inpatient setting. 
1) Day before the start of dose escalation 
Subjects who have already switched to outpatient treatment should be rehospitalized 
by the day before dose escalation is scheduled to start as specified in Section 3.2.5. 
The investigator or subinvestigator will perform the following assessments on the day 
before the dose escalation is scheduled to start. If these procedures have already been 
performed on the same day, they do not need to be repeated. 


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 Serum sodium concentration (at predose) 
 Clinical symptoms associated with hyponatremia (at a feasible time) 
2) Start of dose escalation to determination of the maintenance dose 
On and after the day of start of an additional dose escalation beyond the once fixed 
maintenance dose,, the investigator or subinvestigator will perform the procedures as 
specified in Section 3.7.1.15, however, measurements of cumulative urine volume 
and fluid intake (daily urine volume, daily fluid intake, daily fluid balance, and urine 
osmolarity) are not required. On scheduled assessment days, the procedures specified 
for each day should be performed. 
3) Redetermination of maintenance dose 
The investigator or subinvestigator will perform the procedures as specified in 
Section 3.7.1.16, when the new maintenance dose is determined. 
On or after the day on which a new maintenance dose is determined, the investigator 
or subinvestigator will perform the procedures specified in Section 3.7.1.17 to make a 
judgement for possibility of switching to outpatient treatment. 
 
3.7.1.19 
Treatment Discontinuation 
When discontinuation of treatment with the IMP is judged to be necessary according to 
Section 3.8.3.1, the investigator or subinvestigator will perform the following 
assessments. If these assessments have already been performed on the same day, they do 
not need to be repeated. If it is not feasible to perform all of the examinations, 
observations, and assessments at discontinuation of treatment, due to the subject’s refusal 
or based on the judgment of the investigator or subinvestigator (eg, in emergencies), only 
those that are feasible should be performed. 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 Serum sodium concentration 
 Body weight 
 Serum osmolality 
 Plasma drug concentration (blood sampling) 
 Laboratory tests (blood/urine sampling) 
 Liver function tests (blood sampling) 
 Vital signs (blood pressure, pulse rate, body temperature) 
 12-Lead electrocardiography 
 Plasma AVP concentration 


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 IMP compliance 
 AEs 
The subject will visit the trial site 3 to 5 days and 7 to 10 days after the final IMP 
administration to undergo the procedures specified in Section 3.7.1.20. 
3.7.1.20 
Follow-up 
3.7.1.20.1 
Serum Sodium Concentration (3 to 5 Days After the Final IMP 
Administration) 
The subject will visit the trial site 3 to 5 days after the final IMP administration (the 
completion of treatment) to undergo the following examinations and investigations. 
 Clinical symptoms associated with hyponatremia 
 Serum sodium concentration 
 AEs 
 
3.7.1.20.2 
Follow-up Examination (7 to 10 Days After the Final IMP 
Administration) 
The subject will visit the trial site 7 to 10 days after the final IMP administration (the 
completion of treatment) to undergo the following examinations and investigations. 
 Confirmation of concomitant drugs and therapies 
 Clinical symptoms associated with hyponatremia 
 Serum sodium concentration 
 Body weight 
 Serum osmolality 
 Laboratory tests (blood/urine sampling) 
 Liver function tests (blood sampling) 
 Vital signs (blood pressure, pulse rate, body temperature) 
 12-Lead electrocardiography 
 Plasma AVP concentration 
 Pregnancy test 
 AEs 
 
If treatment with the IMP was completed before the duration of treatment reached 30 
days (except for treatment discontinuations specified in Section 3.8.3.1) and 
hyponatremia then recurred, and the investigator or subinvestigator concludes that 
readministration of IMP is necessary, treatment may be resumed within 30 days after the 
initial IMP administration (for the readministration procedure, see Appendix 3). If the 


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investigator or subinvestigator judges not to resume treatment with the IMP, the follow- 
up period for the subject is to be completed. 
The subject may be asked to revisit the trial site to repeat the follow-up examination, if 
those examinations are necessary for the investigator or subinvestigator to determine 
whether readministration should be started. 
3.7.2 
Efficacy Assessments 
 
3.7.2.1 
Serum Sodium Concentration 
For the efficacy evaluation, serum sodium concentrations will be measured centrally at 
the contract research organization for clinical laboratory tests (hereafter, central 
laboratory). In addition, because the investigator or subinvestigator must be apprised of 
the serum sodium concentrations in a timely manner to conduct the assessment of 
eligibility, decisions of switching to outpatient treatment, and the dose selection of 
tolvaptan, as well as to ensure subject safety, serum sodium concentrations will also be 
measured at each trial site from the screening period to the follow-up period. 
The central laboratory will measure serum sodium concentrations according to the 
procedures specified by the laboratory, and provide the measurement results to the 
sponsor and the investigator or subinvestigator. The investigator or subinvestigator will 
document blood sampling, as well as the date and time of sampling in the CRF. The 
electronic file submitted to the sponsor by the central laboratory will be regarded as the 
source document; therefore, recording of the results in the CRF is unnecessary. At the 
same blood sampling points as those specified in Section 3.7.3.2, the serum sodium 
concentration data obtained as part of the clinical laboratory tests at the central laboratory 
will be used. 
In the measurement of serum sodium concentrations, each trial site should use 
appropriate equipment and apparatuses, with reliable precision, and follow the procedures 
specified by the site. Measured values (with the unit) obtained at the trial site, as well as 
the time and date of measurement, should be recorded in the source document and CRF. 
3.7.2.2 
Clinical Symptoms Associated With Hyponatremia 
The investigator or subinvestigator will interview the subject to confirm whether the 
clinical symptoms associated with hyponatremia (anorexia, vomiting, headache, 
consciousness disturbed, and malaise)11,12 are present and their severities along with the 
general condition of subjects, and record whether the interview was conducted, the date 
of interview, and presence or absence of clinical symptoms (if present, its severity of 


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each symptom is to be recorded based on the following gradings) in the source document 
and CRF. 
1) Anorexia11 
 Grade 1 
Loss of appetite without an alteration in eating habits 
 Grade 2 
Oral intake altered without significant weight loss or malnutrition; oral nutritional 
supplements indicated 
 Grade 3 
Associated with significant weight loss or malnutrition (eg, inadequate oral caloric 
and/or fluid intake); intravenous fluid, tube feeding, or TPN indicated 
2) Vomiting11 
 Grade 1 
1 to 2 episodes (separated by 5 minutes) in 24 hours 
 Grade 2 
3 to 5 episodes (separated by 5 minutes) in 24 hours 
 
 Grade 3 
≥6 episodes (separated by 5 minutes) in 24 hours 
3) Headache11 
 Grade 1 
Mild pain 
 Grade 2 
Moderate pain; limits instrumental activities of daily living (ADL) 
 Grade 3 
Severe pain; limits self care ADL 
4) Consciousness disturbed12 
 I = Awakens in the absence of a stimulus 
 1. Not fully conscious 
 2. Disoriented 
 3. Not able to say one’s own name or birth date 
 II = Awakens in the presence of a stimulus 
 10. Opens eyes easily when addressed with a regular speaking voice. 


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 20. Opens eyes when addressed with a loud voice or continuously shaken. 
 30. Opens eyes slightly when repeatedly addressed, while giving a pain 
stimulus. 
 III = Does not awaken in the presence of a stimulus 
 100. Motions as if brushing away a pain stimulus 
 200. Moves a limb slightly or winces at a pain stimulus 
 300. Displays no response to a pain stimulus 
5) Malaise11 
 Grade 1 
Uneasiness or lack of well being 
 Grade 2 
Uneasiness or lack of well being; limits instrumental ADL 
3.7.3 
Safety Assessments 
 
3.7.3.1 
Adverse Events 
See Section 5. 
3.7.3.2 
Clinical Laboratory Tests 
Blood and urine samples for clinical laboratory tests will be collected, and the time and 
date of blood sampling, and the date of urine collection will be recorded in the source 
document. The samples will be sent to the specified central laboratory for central 
measurements. The central laboratory will measure the laboratory test parameters 
presented in Table 3.7.3.2-1 according to the procedures specified by the laboratory, and 
provide the results of the measurements to the sponsor and the investigator or 
subinvestigator. The investigator or subinvestigator will document blood or urine 
samplings, as well as the dates and times for blood samples and the dates for urine 
samples in the CRF. The electronic file submitted to the sponsor by the central laboratory 
will be regarded as the source document; therefore, recording of the results in the CRF is 
unnecessary. 
Unscheduled clinical laboratory tests, if required at the occurrence of AEs or for the 
follow-up of AEs, should be performed centrally at the specified central laboratory, 
except in emergencies, in which case clinical laboratory tests may be performed at each 
trial site. 


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a 
PT: Prothrombin time 
bγ-GTP: gamma glutamyl transpeptidase 
c 
CK (CPK): Creatine kinase (creatine phosphokinase) 
dSerum cortisol: measured only at the screening examination 
 
The total volume of blood collected throughout the trial from a subject treated with the 
IMP for 30 days is at least approximately 175 mL (for hematology, serum chemistry 
[including central measurements of serum sodium concentration], and measurements of 
serum osmolality, plasma AVP concentration, and plasma drug concentration). In 
addition, the following blood samplings may be added. 
 Blood samplings for central measurements of serum sodium concentration for the 
efficacy evaluation 
 Blood samplings for measurements of serum sodium concentration at the trial site 
(see Section 3.7.2.1) 
 Blood sampling for pregnancy tests (only in female subjects of childbearing potential) 
If the subject is a woman of childbearing potential, a pregnancy test should be performed 
at the screening examination and the result must be obtained before start of IMP 
administration. 
Table 3.7.3.2-1 
Clinical Laboratory Assessments 
Hematology 
Serum Chemistry 
Alkaline 
phosphatase γ-GTPb 
Lactic dehydrogenase 
CK (CPK)c 
Total protein 
Albumin 
Random glucose 
Total cholesterol 
Triglycerides 
Urea nitrogen 
Creatinine 
Uric acid 
Serum electrolytes (Na, K, Cl) 
Transferrin 
Serum cortis   d 
ol 
Liver function tests 
AST (GOT) 
ALT (GPT) 
Serum total bilirubin 
Additional tests 
Serum hCG pregnancy test for female subjects of 
childbearing potential 
Red blood cell count 
Hemoglobin 
Hematocrit 
Leucocyte count 
Differential leukocyte count (neutrophils, 
eosinophils, basophils, monocytes, and 
lymphocytes) 
Platelet count 
PT (seconds, INR)a 
Urinalysis 
Qualitative urinalysis 
pH 
Protein 
Glucose 
Occult blood 
Ketone bodies 
Bilirubin 
Urobilinogen 


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3.7.3.3 
Body Weight 
Body weight will be measured using a scale with appropriate maintenance with a 
minimum division of 0.1 kg, while minimizing the influence of clothing. The date, time, 
and result (expressed in 0.1 kg intervals) of the measurement will be recorded in the 
source document and CRF. The result should be rounded to 1 decimal place. 
When body weight is measured during an outpatient visit, the influence of clothing 
should be minimized. 
3.7.3.4 
Vital Signs 
3.7.3.4.1 
Body Temperature 
Axillary temperature will be measured using an appropriately maintained thermometer, 
and the completion status (with or without measurement), date, time, and result of the 
measurement will be recorded in the source document and CRF. The result should be 
rounded to 1 decimal place. 
3.7.3.4.2 
Blood Pressure and Pulse Rate 
Blood pressure (systolic and diastolic) and pulse rate will be measured after the subject 
has been sitting for at least 3 minutes, using appropriately inspected instruments. The 
status (measured/not measured), date, time, and results of the measurements will be 
recorded in the source document and CRF. 
3.7.3.5 
12-Lead Electrocardiography 
A resting 12-lead electrocardiogram will be recorded using an appropriately inspected 
electrocardiograph, according to the procedures specified by the trial site. The status 
(measured/not measured) and date of the recording, along with the heart rate, PR interval, 
QRS axis, and QT interval, as well as the interpretation (normal or abnormal [detailed 
findings, if abnormal]) of the investigator or subinvestigator will be recorded in the 
source document and CRF. 
3.7.3.6 
Pregnancy Test 
1) Subjects requiring a pregnancy test 
Female subjects of childbearing potential at the time of the pregnancy test 
The following female subjects are considered to be women of nonchildbearing 
potential, and do not need to undergo pregnancy test. 
 Women who have undergone a hysterectomy or bilateral ovariectomy 


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2) Methods 
A blood sample for a serum hCG pregnancy test will be collected from a female 
subject of childbearing potential. The sample will be sent to the specified central 
laboratory for central measurement. The central laboratory will perform the test 
according to the procedures specified by the laboratory, and report the result to the 
sponsor and the investigator or subinvestigator. The investigator or subinvestigator 
will record the date and time of blood sampling, and the interpretation of the 
investigator or subinvestigator (pregnancy suspected/not suspected) in the source 
document. The investigator or subinvestigator will record the status (with or without 
blood sampling), date, and time of blood sampling, and the interpretation of the 
investigator or subinvestigator in the CRF. The electronic file submitted to the 
sponsor by the central laboratory will be regarded as the source document; therefore, 
recording of the result in the CRF is unnecessary. If the investigator or 
subinvestigator suspects pregnancy, administration of the IMP to the subject should 
be discontinued as 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 
On Day 21 of treatment period and the day after the final IMP administration, and at 
discontinuation of treatment, a blood sample will be collected using a heparin sodium- 
containing test tube. 
All of the blood samples will be sent to and analyzed at the bioanalytical laboratory. For 
detailed procedures regarding handling and shipment of the blood samples, see Appendix 
2. 
3.7.4.2 
Pharmacodynamic Assessments 
3.7.4.2.1 
Daily Urine Volume 
During the pretreatment observation period, daily urine volume will be measured for the 
time interval starting at immediately after complete urination after breakfast and ending 
at complete urination immediately before the IMP administration on the following day. 
After the initial IMP administration on Day 1 of treatment period through determination 
of the maintenance dose, daily urine volume will be determined for each time interval 
from the point after complete urination immediately before the IMP administration of the 
day to the point after complete urination immediately before the IMP administration on 
the following day. 


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The status (measured/not measured), start date and time, and completion date and time of 
measurement, and the daily urinary volume will be recorded in the source document and 
CRF. 
3.7.4.2.2 
Daily Fluid Intake 
Daily fluid intake (juice, milk, tea, water, transfusion, etc.) will be determined for the 
same intervals as the measurement of daily urine volume. During the pretreatment 
observation period, daily fluid intake will be determined for the time interval starting at 
immediately after complete urination after breakfast and ending at complete urination 
immediately before the IMP administration on the following day. After the initial IMP 
administration on Day 1 of treatment period through the determination of maintenance 
dose, daily fluid intake will be determined for each time interval from the point after 
complete urination immediately before the IMP administration of the day to the point 
after complete urination immediately before the IMP administration on the following day. 
The status (measured/not measured), start date and time, and completion date and time of 
measurement, and the daily fluid intake will be recorded in the source document and CRF. 
Water that the subject drinks with the IMP will be included in the fluid intake after the 
IMP administration. 
3.7.4.2.3 
Daily Fluid Balance 
Daily fluid balance will be calculated by deducting “daily urine volume” from “daily 
fluid intake.” The daily fluid balance will be calculated by the sponsor; therefore, entry of 
daily fluid balance in the CRF is unnecessary. 
3.7.4.2.4 
Serum Osmolality 
A blood sample will be collected for the measurement of serum osmolality, and the date 
and time of blood sampling will be recorded in the source document. Serum osmolality 
will be measured centrally by the central laboratory according to the procedures specified 
by the laboratory. The central laboratory will report the result of the measurement to the 
sponsor and the investigator or subinvestigator. The investigator or subinvestigator will 
document blood sampling, as well as the date and time of sampling in the CRF. The 
electronic file submitted to the sponsor by the central laboratory will be regarded as the 
source document; therefore, entry of the result in the CRF is unnecessary. 


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3.7.4.2.5 
Urine Osmolality 
1) Urine sample processing (screening period) 
A urine sample will be collected for the measurement of urine osmolality and stored 
in a refrigerator. The status (urine sample collected/not collected) and date of urine 
collection will be recorded in the source document and CRF. 
2) Urine sample processing (pretreatment observation period and treatment period) 
An approximately 5 mL aliquot of cumulative urine sample will be taken in a sample 
stock tube and stored in a refrigerator. The date of urine collection will be recorded in 
the source document. Before taking the aliquot, the cumulative urine volume will be 
measured. 
3) Measurement of urine osmolality 
The urine samples will be sent to the specified central laboratory where urine 
osmolality is measured centrally according to the procedures specified by the 
laboratory. The central laboratory will report the measurement results to the sponsor 
and the investigator or subinvestigator. The electronic file submitted to the sponsor by 
the central laboratory will be regarded as the source document; therefore, entry of the 
result in the CRF is unnecessary. 
3.7.4.2.6 
Daily Urinary Sodium Excretion 
1) Urine sample processing (screening period) 
A urine sample will be collected for the measurement of urine sodium concentration 
and stored in a refrigerator. The date of urine collection will be recorded in the source 
document. 
2) Urine sample processing (pretreatment observation period and treatment period) 
An approximately 5 mL aliquot of cumulative urine sample will be taken in a sample 
stock tube and stored in a refrigerator. The date of urine collection will be recorded in 
the source document. Before taking the aliquot, the cumulative urine volume will be 
measured. 
3) Measurement of urine sodium concentration 
The urine samples will be sent to the specified central laboratory where urine sodium 
concentration is measured centrally according to the procedures specified by the 
laboratory. The central laboratory will report the measurement results to the sponsor 
and the investigator or subinvestigator. The electronic file submitted to the sponsor by 
the central laboratory will be regarded as the source document; therefore, entry of the 
result in the CRF is unnecessary. 


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4) Calculation of urinary sodium excretion 
Daily urinary sodium excretion will be calculated by multiplying the urinary sodium 
concentration by the daily urine volume. Daily urinary sodium excretion will be 
calculated by the sponsor; therefore, entry of the daily urinary sodium excretion in the 
CRF is unnecessary. 
3.7.4.2.7 
Plasma Arginine Vasopressin Concentration 
A blood sample will be collected for the measurement of plasma AVP concentration, and 
the date of blood sampling will be recorded in the source document. The sample will be 
sent to the specified central laboratory for central measurement. The central laboratory 
will measure the plasma AVP concentration according to the procedures specified by the 
laboratory, and report the result to the sponsor and the investigator or subinvestigator. 
The investigator or subinvestigator will record the status (blood sample collected or not 
collected), date, and time of blood sampling in the CRF. The electronic file submitted to 
the sponsor by the central laboratory will be regarded as the source document; therefore, 
entry of the result in the CRF is unnecessary. 
If the plasma AVP concentration was measured as part of routine medical practice at the 
trial site prior to a subject’s participation in the trial, and that result was used for the 
subject’s eligibility assessment, the date of the blood sampling and the results will be 
recorded in the source document and CRF. 
3.7.5 
End of the Trial 
 
The “End of trial date” is defined as the date on which the last subject completes the trial. 
3.8 
Discontinuation 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 Trial Sites 
 
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 trial site will notify 
the sponsor promptly if the trial is terminated by the investigator or the IRB at the site. 


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3.8.3 
Individual Subject Discontinuation 
 
3.8.3.1 
Treatment Discontinuation 
In the cases listed below, treatment with the IMP should be discontinued and the 
examination at withdrawal specified in Section 3.7.1 should be performed. In such cases, 
the investigator or subinvestigator will find out the situation in detail, and record the date 
and reason for discontinuation in the source document and CRF. 
1) 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 infeasible due to the occurrence of AEs. 
4) Laboratory test results (AST [GOT] or ALT [GPT]) were ≥3 times the upper limit 
of normal (ULN) at the trial site or the specified central laboratory. 
5) Serum sodium concentration increased by ≥12 mEq/L from predose, within 24 
hours after IMP administration. 
6) Serum sodium concentration exceeding 145 mEq/L is observed during the 
treatment period. 
7) The subject becomes poorly compliant with treatment without taking the IMP for 
≥7 consecutive days. 
8) Pregnancy is suspected or confirmed. 
9) The investigator or subinvestigator judges that withdrawal is necessary for any 
other reason. 
Administration of the IMP to the subject may be discontinued after the start of treatment 
for a variety of reasons. Treatment may be discontinued due to an unsatisfactory effect of 
the IMP (at the subject’s request), due to the occurrence of an AE, because the use of 
prohibited concomitant medications or therapies has become necessary, or because the 
investigator or subinvestigator has concluded discontinuation of treatment to be 
medically necessary for other reasons. In any case, the option to continue treatment with 
the IMP should be offered to the subject, whenever possible, as described in 
Section 3.8.3.4. 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation 
Subjects may discontinue treatment for the reasons listed below. 
 Reasons related to AEs: 
 Subject decides to discontinue due to annoyance or discomfort resulting from a 
nonserious AE that is not otherwise determined to be an undue hazard 
 Continuing treatment with the IMP places the subject at an undue risk as 
determined by the investigator or subinvestigator 


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 A serious adverse event (SAE) 
 Laboratory test results (AST [GOT] or ALT [GPT]) becomes ≥3 times the 
ULN at the trial site or the specified central laboratory. 
 Serum sodium concentration increased by ≥12 mEq/L from predose, within 24 
hours after IMP administration. 
 Serum sodium concentration exceeds 145 mEq/L during the treatment period. 
 Other safety concerns or AEs that may possibly be related to the IMP 
 Death 
 Loss to follow-up of the subject 
 Poor treatment compliance 
 Pregnancy (see Section 5.5) 
 Major protocol deviations 
 Withdrawal of informed consent (complete written withdrawal of consent form) 
 Premature termination of all or part of the trial by the sponsor 
 Other reasons unrelated to medical condition 
(including cases in which the subject has been found, after the start of treatment to 
deviate from any of the inclusion criteria or meet any of the exclusion criteria) 
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 subjects have the right to withdraw their consent from further participation in the trial 
at any time and without prejudice. Subjects cannot withdraw consent for use of data 
already collected as part of the trial, but only for future participation. The investigator or 
subinvestigator can also discontinue a subject’s participation in the trial at any time if 
medically necessary. Unless the subject provides their written withdrawal of consent or 
there is other written documentation by the investigator or subinvestigator confirming the 
subject’s verbal intent to completely withdraw from the trial, subjects should be followed 
for all protocol-specified evaluations and assessments, if possible. 
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial ICF): 
 Participation in all follow-up procedures specified in the protocol (whether at the trial 
site, by telephone, or by an in-home visit) 
 Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff) 


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 Contact of the subject by trial personnel, even if only by telephone, to assess the 
subject’s current medical condition and obtain necessary medical or laboratory 
reports relevant to the trial’s objectives. 
 Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician) 
 Access to medical information from alternative sources (eg, hospital/clinic medical 
records, the referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, or social media sources) 
 
Withdrawal of consent is a critical trial event and, therefore should be approached with 
the same degree of importance and care as used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express a desire to discontinue IMP administration, which is not 
equivalent to a complete withdrawal of consent for further participation (see 
Section 3.8.3.1). A subject may, however, indicate that further trial participation is 
creating a burden on their work or social schedule. Therefore, the investigator or 
subinvestigator should follow the procedures outlined in Section 3.8.3.2 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 subjects who withdraw their 
permission for all of the above degrees of follow-up are considered to have completely 
withdrawn their consent to participate in the trial. 
3.8.3.4 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, the investigator or 
subinvestigator will meet and discuss with the subject at the trial site or by telephone the 
option of continuing participation 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 Failure 
 
A screen failure is defined as a subject who consented to participate in the trial and 
signed informed consent, but received no dose of the IMP. 
A subject who signed an informed consent but received no dose of the IMP may be 
rescreened according to Section 3.4.3. 


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For a subject who meets the definition of screen failure, the following items will be 
recorded in the CRF for screen failure. 
 Day of investigation 
 Date the subject was determined to be a screen failure 
 Date the subject provided informed consent 
 Birth date 
 Gender 
 Race 
 Ethnicity 
 Compliance with the inclusion criteria (Record the number of the criterion the subject 
did not meet, if any) 
 Deviation from the exclusion criteria (Record the number of the criterion the subject 
met, if any) 
 Reasons for screen failure 
 
3.10 
Definition of Completed Subjects 
 
A trial completer is defined as a subject who received at least 1 dose of the IMP and 
underwent the examination on the day after the final IMP administration. 
3.11 
Definition of Subjects Lost to Follow-up 
 
Subjects who cannot be contacted on or before Day 30 during the treatment period, who 
does not have a known reason for discontinuation (eg, withdrew consent or AE), and for 
whom survival status at the end of the trial cannot be determined will be classified as 
“lost to follow-up” as the reason for discontinuation. Survival status can be determined 
from a variety of sources, either by obtaining acceptable documentation of death (ie, 
death certificate, medical records, public records, or a 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, a 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. Further, in the event the investigator, subinvestigator, or 
designee is unable to reach the subject by telephone, they will attempt to contact the 
subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status. 
The investigator or subinvestigator will record the items listed below for a subject who is 
lost to follow-up in the source document and CRF. 


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 Day of investigation 
 Investigation methods 
 Contact with the subject (successful/unsuccessful) 
 Reason why the subject does not (cannot) visit 
 Confirmation of treatment compliance 
 Presence or absence of an AE (if present, specify the name, dates of onset and 
disappearance, severity, and causal relationship with the IMP, of the event) 
 Action taken with the IMP, and treatment for and outcome of the event 
 If an investigation is impossible, specify the reason. 
 
3.12 
Subject Compliance 
 
The subject will be placed under the management of the investigator or subinvestigator 
during the trial. The investigator or subinvestigator will instruct the subject to adhere to 
the following. 
 The subject should take the IMP according to the specified dosage regimen. 
 The subject should adhere to the specified schedule during the trial. 
 The subject should not use the prohibited concomitant medications (see Section 4.1). 
 The subject should adhere to the specified fluid intake restriction (see Section 4.2). 
 The subject should not divulge information obtained as a result of participation in the 
trial 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 from the sponsor, and 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 
the subjects. In such cases, the investigator or subinvestigator should promptly submit a 
document stating the details of and reasons for the deviation or change to the sponsor and 
the head of the trial site, and obtain the approval of the IRB. In addition, the investigator 
or subinvestigator should receive approval from the head of the trial site, and obtain the 
written agreement of 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, a violation of the informed consent process, IMP dispensing 


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or dosing error, treatment assignment error, subject enrollment in violation of the 
eligibility criteria or concomitant medication criteria), the investigator, 
subinvestigator, or designee will contact the sponsor at the earliest possible time by 
telephone. The investigator or subinvestigator and sponsor will come as quickly as 
possible to a joint decision regarding the subject’s continued participation in the trial. 
This decision will be documented by the investigator or subinvestigator and the 
sponsor, and reviewed by the site monitor. 
2) Record of deviations 
The investigator or subinvestigator will record all deviations from the protocol in the 
source document. 
In addition, the investigator or subinvestigator will record certain specified protocol 
deviations in the CRF, according to the written procedures for preparation of the CRF 
supplied by the sponsor. 
3.14 
Investigation of Treatment Compliance 
 
The investigator or subinvestigator will ask the subject if the IMP was taken as specified, 
and record the date of dosing (as well as the time during hospitalization) and daily dose 
taken in the source document and CRF. 
 
 
4 
Restrictions 
4.1 
Prohibited Concomitant Medications 
 
If any medication other than the IMP was used from the day informed consent was 
obtained to the day the trial was completed, the name, indication, dosage regimen, daily 
dose, administration route, and dates the medication started and ended will be recorded in 
the source document and CRF. For therapies other than medications, the name, indication, 
and dates the therapy started and ended will be recorded in the source document and CRF. 
From the pretreatment observation period (the day before start of IMP administration) to 
the completion of the final IMP treatment, the concomitant use of the drugs listed in 
Table 4.1-1 and Table 4.1-2 is prohibited. The use of hypertonic saline to correct serum 
sodium concentration is prohibited from the time informed consent is obtained until the 
completion of IMP administration, except in cases of absolute necessity (eg, treatment for 
AEs). 


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a 
Human immunodeficiency virus 
bAdrenocorticotropic hormone 
Table 4.1-1 
List of Medications Prohibited During the Trial 
 
Demeclocycline 
 
Lithium carbonate 
 
Urea 
 
The following drugs used to correct serum sodium concentration: 
 
Intravenous saline 
 
Hypertonic saline 
 
Drugs and foods that may be a strong inhibitor or inducer of CYP3A4 (see Table 4.1-2) 
 
Drug products containing tolvaptan other than the IMP, mozavaptan hydrochloride 
 
Drugs unapproved in Japan 
Table 4.1-2 
Drugs and Foods That May Be Strong Inhibitors or Inducers 
of CYP3A4 
Drug class 
Drugs 
1) CYP3A4 inhibitors (excluding external use 
agents) 
Antimicrobials 
Clarithromycin, 
 erythromycin, 
itraconazole, 
miconazole, 
chloramphenicol, 
 voriconazole, 
ciprofloxacin, fosfluconazole 
fluconazole, 
norfloxacin, 
telithromycin, 
Ca antagonists 
Diltiazem, verapamil 
Antidiabetic 
Glibenclamide 
Immunosuppressant 
Cyclosporine 
Anticancer agents 
Imatinib, crizotinib 
Anti-H 
a drugs 
IV 
Indinavir, nelfinavir, ritonavir, saquinavir, delavirdine, 
atazanavir, 
fosamprenavir, 
lopinavir, 
darunavir, 
telaprevir, cobicistat 
Autonomic drug 
Tofisopam 
Adenosine A2A receptor antagonist 
Istradefylline 
Antimetic 
Aprepitant 
Drug for a pituitary ACT   b secretion test 
H 
Metyrapone 
2) CYP3A4 inducers (excluding external use 
agents) 
Barbiturates 
Phenobarbital, amobarbital, pentobarbital, barbital, 
secobarbital 
Antiepileptics 
Carbamazepine, phenytoin 
Antitubercular agents 
Rifampicin, rifabutin 
Psychostimulant 
Modafinil 
Anti-HIV drugs 
Efavirenz, nevirapine, etravirine 
Endothelin receptor antagonist 
Bosentan 
3) Foods containing 
CYP3A4 
substances   that   inhibit 
Grapefruit, Seville 
processed products 
orange, star fruit, and their 
4) Foods containing 
CYP3A4 
substances that induce 
St. John’s Wort-containing foods 


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4.2 
Fluid Intake Restriction 
 
1) From the acquisition of informed consent to the end of the pretreatment 
observation period (the day before start of IMP administration) 
Fluid intake will be restricted to a daily fluid intake of ≤20 mL/kg. 
2) Within 24 hours after the IMP administration on Day 1 of treatment period 
Fluid intake must not be restricted. 
3) From the IMP administration on Day 2 of treatment period to the day after the 
final IMP administration 
Setting the fluid intake volume from immediately before IMP administration on Day 
1 of treatment period to immediately before IMP administration on Day 2 of 
treatment period as the upper limit of daily fluid intake, subjects will be instructed to 
restrict fluid intake. Fluid intake is the total volume of beverages (eg, juice, milk, tea), 
water, and transfusions, not including solid food-derived fluids. 
The investigator or subinvestigator should pay attention to an excessive increase in 
urine volume or rapid increase in serum sodium concentration. If thirst or dehydration, 
and other unfavorable symptoms develop, the investigator or subinvestigator should 
instruct the subject to take more fluids, regardless of the upper limit of daily fluid 
intake to ensure the safety of the subject. 
The investigator or subinvestigator will ask the subject whether he/she has complied 
with the fluid intake restriction, and record the period of assessment (dates of start 
and completion) and the result in the source document and CRF. 
4) From the completion of the examination on the day after the final IMP 
administration to the completion of the follow-up examination 
Fluid intake will be restricted to a daily fluid intake of ≤20 mL/kg. 
 
 
5 
Reporting of Adverse Events 
5.1 
Definition 
 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered an IMP and which does not necessarily have a causal relationship with this 
treatment. Adverse events would not include information recorded as medical history at 
screening for pre-planned procedures for which the underlying condition was known and 
no worsening occurred. An adverse reaction is any untoward and unintended response to 
an IMP related to any dose administered. 


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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 
 Requires inpatient hospitalization or prolongs hospitalization. 
 Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported. 
 Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical 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. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
Immediately reportable event (IRE): 
 Any SAE. 
 Any AE related to occupational exposure. 
 Potential drug-induced liver injury (DILI) (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 be documented on the “Adverse event” section of the 
CRF only if there is an abnormality or complication. 
 
Changes in clinical laboratory tests: It is the investigator or subinvestigator’s 
responsibility to review the results of all laboratory tests as they become available. This 
review will be documented by the investigator or subinvestigator’s dated signature on the 


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laboratory report. For each abnormal laboratory test result, the investigator or 
subinvestigator needs to ascertain if this is an abnormal (ie, clinically significant) change 
from baseline for that individual subject. This determination, however, does not 
necessarily need to be made the first time an abnormal value is observed. The 
investigator or subinvestigator may repeat the laboratory test or request additional tests to 
verify the results of the original laboratory tests. If this laboratory value is considered 
medically relevant by the investigator or subinvestigator (the subject is symptomatic, 
requiring corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation and/or fulfills a seriousness criterion, this is considered an AE. 
 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the CRF. The intensity of an adverse experience is defined as follows: 
1 = Mild: 
Discomfort noticed, but no disruption to daily activity. 
2 = Moderate:  Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: 
Inability to work or perform normal daily activity. 
 
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE. 
Not related: 
There is no temporal or causal relationship between the IMP and the 
AE. 
5.2 
Eliciting and Reporting Adverse Events 
 
The investigator or subinvestigator will regularly assess subjects for the occurrence of 
AEs. To avoid bias in eliciting AEs, subjects should be asked the nonleading question: 
“How have you felt since your last visit?” All AEs (serious and nonserious) reported by 
the subject from the time of the acquisition of informed consent to the completion of the 
trial must be recorded in the source document and CRF provided by the sponsor. 
Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms. Exacerbation or disease progression should 
be reported as an AE only if there are unusual or severe clinical features that were not 
present, not experienced earlier, or not expected based on the course of the condition. If 


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an AE that has been previously reported worsens and its severity or seriousness changes, 
it will be recorded as a new AE in the CRF. 
In addition, the sponsor must be notified immediately by e-mail, as a rule, of any IREs, 
according to the procedure outlined in Section 5.3 Immediately Reportable Events. 
Special attention should be paid to recording hospitalization and concomitant medications. 
In the CRF, the following items should be recorded according to the written procedures 
for preparation of the CRF provided by the sponsor. 
 Name of the event 
 Dates of onset (as well as time, if possible, during hospitalization) and 
recovery/resolution 
 Severity 
 Seriousness (if serious, specify the details) 
 Causal relationship with the IMP 
 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, as a rule, to the 
sponsor using the contact information on the cover page of this protocol. 
An immediately reportable event: 
 Any SAE. 
 Any AE related to occupational exposure. 
 Potential drug-induced liver injury (DILI) (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 be documented in the “Adverse event” section of the 
CRF only if there is an abnormality or complication. 
In addition, the IRE form should be filled out and sent to the sponsor by e-mail, as a rule. 
It should be noted that the IRE form is not the “Adverse event” section of the CRF. 
A subject experiencing an SAE should be followed until the event has been resolved or 
clinically stabilized, or until the subject is lost to follow-up. When the subject’s health 
condition returns to baseline status, the event is considered to have been resolved. When 
no further improvement or deterioration of the subject’s health condition is expected, in 
the opinion of the investigator or subinvestigator, the event is considered to have 


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stabilized. The investigator or subinvestigator will provide appropriate treatment for the 
subject and convey prompt updates on the subject’s status to the sponsor. 
5.4 
Potential Drug-Induced Liver Injury 
 
The total bilirubin level should also be evaluated for any subject who experiences an 
elevation in AST or ALT that is ≥3 times the ULN. If the subject’s total bilirubin is ≥2 
times the ULN, the investigator or subinvestigator should record all of the laboratory 
values in an IRE form, and promptly send it to the sponsor according to the procedures 
specified in Section 5.3. 
5.5 
Pregnancy 
 
Women of child-bearing potential are defined as female subjects for whom menstruation 
has started and who have not been documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy). 
For both women of child-bearing potential and men who are sexually active, there must 
be a documented agreement that the subject and/or their partner will take effective 
measures to prevent pregnancy during the course of the trial and for 30 days after the l 
final IMP administration. Unless the subject is sterile (ie, women who received a bilateral 
oophorectomy and/or hysterectomy, or men who have had a bilateral orchidectomy) or 
remains abstinent, at least one of the following contraceptive measures must be used: a 
vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pills, or 
condom with spermicide. 
Before enrolling a woman of childbearing potential in this clinical trial, the investigator 
or subinvestigator must review the guidelines regarding trial participation for women of 
childbearing potential. The topics should generally include: 
 General information 
 Informed consent form 
 Information on contraception 
 Drug interactions with hormonal contraceptives 
 Contraceptives in current use 
 Guidelines for the follow-up of a reported pregnancy 
Before enrollment in the trial, a woman of childbearing potential must be advised of the 
importance of avoiding pregnancy during trial participation and the potential risk factors 
for an unintentional pregnancy, and must sign an ICF stating that the above mentioned 
risk factors and the consequences were discussed with her. 


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A serum hCG pregnancy test will be performed at the time of screening on all female 
subjects of childbearing potential. If the investigator or subinvestigator suspects 
pregnancy based on the test result, the subject should be excluded from the trial 
according to Section 3.4.3, without administering the IMP to the subject. 
During the trial, all female subjects of childbearing potential should be instructed to 
contact the investigator or subinvestigator immediately if they suspect that they might be 
pregnant (eg, missed or late menstrual cycle). 
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy test 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, treatment with the IMP 
must be withheld immediately (if reasonable, taking into consideration any potential 
withdrawal risks) until the result of the pregnancy test is known. If pregnancy is 
confirmed, the IMP will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject’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 exposure to the IMP during the trial and for at least 30 days 
after the final dose of the IMP, and record the event on the IRE form and forward it to the 
sponsor. The sponsor will forward the Pregnancy Surveillance Form(s) for monitoring the 
outcome of the pregnancy. 
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator or subinvestigator must report to the sponsor, on the Pregnancy Surveillance 
Form(s), follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome. Infants will be followed for a minimum of 6 months 
from the date of birth. 
5.6 
Procedure for Breaking the Blind 
 
Not applicable 
5.7 
Follow-up of Adverse Events 
 
In this trial, information on AEs will be collected until the follow-up examination, 
performed 7 to 10 days after the final IMP administration (hereinafter, referred to as the 
“trial completion day”). 


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If any of Section 5.7.1, Section 5.7.2, or Section 5.7.3 are met, the AEs will be followed 
up as specified, after the trial completion day. 
5.7.1 
Follow-up of Nonserious Adverse Events 
 
Nonserious AEs that are identified at any time during the trial must be recorded in the 
Adverse Event section of the CRF. A subject who has any AE or has not recovered from 
any AE at the trial completion day will be followed up at least every 4 weeks, until the 
AE has resolved or clinically stabilized, or until the subject is lost to follow-up. All 
nonserious events that are persistent on the trial completion day will be recorded as 
ongoing in the CRF. For any AE that has been identified throughout the trial, during the 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as risk- 
related behavior, family history, and occupation). Follow-up information collected after 
the trial completion day will be recorded in the medical record. 
5.7.2 
Follow-up of Serious Adverse Events 
 
This trial requires that subjects be actively monitored for SAEs up to the trial completion 
day. A subject who has any AE or has not recovered from any AE at the trial completion 
day will be followed up at least every 4 weeks, until the AE has resolved or clinically 
stabilized, or until the subject is lost to follow-up. 
An SAE that is identified or is persistent on the trial completion day should be recorded 
in the Adverse Event section of the CRF and reported to the sponsor, according to the 
procedures specified in Section 5.3. All SAEs that are persistent on the trial completion 
day will be recorded as ongoing in the CRF. The SAEs to be reported are those that have 
been previously reported but have not yet resolved, and those that are newly identified. 
The investigator or subinvestigator should follow up these SAEs until the events have 
resolved or clinically stabilized, or until the subjects are lost to follow-up, and report 
important update information to the sponsor through the IRE form. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring 
After the Trial Completion Day 
 
Any new SAE that is reported to the investigator or subinvestigator by a subject, which 
occurs after the trial completion day and is determined by the investigator or 
subinvestigator to be related to the IMP, should be reported to the sponsor. The 
investigator or subinvestigator should follow up all SAEs identified after the trial 
completion day until the events have resolved or clinically stabilized, or until the subjects 
are lost to follow-up, and report important update information to the sponsor through an 
IRE form. 


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6 
Pharmacokinetic/Pharmacodynamic Analysis 
6.1 
Pharmacokinetic Analysis 
 
In the pharmacokinetic analysis set (see Section 7.2.4), the plasma concentrations of 
tolvaptan and its metabolites, DM-4103 and DM-4107, on Day 21, at discontinuation of 
treatment, and on the day after the final IMP administration will be adjusted for the dose 
administered immediately before each timepoint to calculate descriptive statistics (n, 
mean, standard deviation, minimum, median, and maximum) by timepoint and by 
compound. 
6.2 
Pharmacodynamic Analysis 
 
In the pharmacodynamic analysis set (see Section 7.2.5), descriptive statistics (n, mean, 
standard deviation, minimum, median, and maximum) for the following parameters will 
be calculated by timepoint. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Serum osmolality 
 Urine osmolality 
 Daily urinary sodium excretion 
 Plasma AVP concentration 
 
7 
Statistical Analysis 
7.1 
Sample Size 
 
The target sample size was determined with respect to the percentage of subjects with a 
normalized serum sodium concentration (≥135 mEq/L) at the final administration of 
tolvaptan. 
Sample size determination was based on the results from patients with SIADH as the 
underlying disease of hyponatremia (“the SIADH subpopulation”) in the efficacy analysis 
sets of 2 overseas phase 3, placebo-controlled, randomized, double-blind trials in patients 
with hyponatremia due to SIADH and other causes (Trials 156-02-235 and 156-03-238, 
with an optional up-titration of 15, 30, and 60 mg for 30 days). To determine the sample 
size of this trial, a threshold percentage was set based on the results of the placebo group 
in the SIADH subpopulation of the overseas trials. Considering the distribution of the 


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point estimates which are calculated based on multiple sample sizes, in the percentage of 
subjects with a normalized serum sodium concentration after the final IMP administration 
in the tolvaptan group, a sample size for which the probability of obtaining a point 
estimate exceeding the threshold percentage was kept at ≥80% was sought. In addition, 
since this trial intends to evaluate the efficacy and safety of tolvaptan in patients with 
SIADH due to a variety of etiologies, and to investigate the appropriateness of the dose- 
titration approach adopted as the dosage regimen, the various etiologies of SIADH and 
the expected number of subjects at each maintenance dose level were also taken into 
consideration in determination of the sample size. 
In the SIADH subpopulation of the 2 overseas phase 3 trials, the percentage of subjects 
with a normalized serum sodium concentration (Day 30, Last Observation Carried 
Forward) was 64.6% (31 of 48 subjects) in the tolvaptan group and 30.2% (16 of 53 
subjects) in the placebo group. Therefore, the threshold percentage was set at 44.3% (the 
upper limit of the exact 95% CI for the percentage of normalized subjects in the placebo 
group). When a binomial distribution with a parameter of 64.6% (the point estimate of 
the percentage of normalized subjects in the tolvaptan group) is assumed, the probability 
that the expected point estimate of the percentage of normalized subjects will exceed the 
threshold percentage is kept at ≥80% with a sample size of ≥8 subjects. 
The underlying diseases of SIADH are diverse, and it is difficult to evaluate the efficacy 
of tolvaptan for each of all SIADH etiologies. Therefore, patients with SIADH will be 
divided into those with SIADH due to ectopic vasopressin producing tumors and those 
due to other etiologies to evaluate the efficacy of tolvaptan. Since the prevalence of these 
2 categories of patients is presumed to be nearly equivalent, a sample size of 16 subjects 
(8 subjects x 2) for the entire trial would enable an efficacy evaluation by SIADH 
etiology. 
In this trial, the following 4 maintenance dose levels have been established: 7.5, 15, 30, 
and 60 mg/day. A sample size for which the probability of obtaining at least 1 subject for 
each maintenance dose level is kept at ≥80% was calculated by applying the multinomial 
distribution. Since the proportion of subjects with each maintenance dose level in the trial 
is unpredictable, the subjects are assumed to be equally distributed to the 4 maintenance 
dose levels. By applying a polynomial distribution with a common parameter of 25% 
across the 4 maintenance dose levels, the sample size required to obtain at least 1 subject 
at each maintenance dose level with a ≥80% probability was 11 subjects. 
Based on the above results, the target sample size has been set as 16 subjects. 


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7.2 
Datasets for Analysis 
 
7.2.1 
Efficacy Analysis Set 
 
The efficacy analysis set consists of all subjects who received at least 1 dose of the IMP 
and have postdose serum sodium concentration data. 
7.2.2 
Maintenance Dose-setting Set 
 
Of the efficacy analysis set, the subpopulation comprised of the subjects for whom 
maintenance doses of the IMP were determined is defined as the maintenance dose- 
setting set. 
7.2.3 
Safety Analysis Set 
 
The safety analysis set consists of all subjects who received at least 1 dose of the IMP. 
7.2.4 
Pharmacokinetic Analysis Set 
 
The pharmacokinetic analysis set consists of all subjects who received at least 1 dose of 
the IMP and have postdose drug concentration data. 
7.2.5 
Pharmacodynamic Analysis Set 
 
The pharmacodynamic analysis set consists of all subjects who received at least 1 dose of 
the IMP and have postdose pharmacodynamic data. 
7.3 
Handling of Missing Data 
 
Missing data on the day after the final IMP administration will be imputed using the last 
available data obtained by the day after the final administration. 
7.4 
Primary and Secondary Endpoint Analyses 
 
The following analyses will be performed in the efficacy analysis set. 
To evaluate the efficacy of tolvaptan in patients who achieved an appropriate 
maintenance dose, the same analyses will also be performed in the maintenance dose- 
setting set. 
In addition, subgroup analyses by SIADH etiology (subjects with SIADH due to ectopic 
antidiuretic hormone-producing tumors/those due to other etiologies) and by serum 
sodium concentration (<130 mEq/L, ≥130 mEq/L) at predose on Day 1 of the treatment 
period will be performed. 
A similar analysis will also be conducted by the dose administered at determination of the 
maintenance dose (7.5, 15, 30, and 60 mg). 


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In the subgroup analyses and the analysis by dose administered at determination of the 
maintenance dose, data obtained at fixing of maintenance dose and the day after the final 
IMP administration will be analyzed. 
In patients receiving readministration with the IMP, similar analyses using the data 
immediately before treatment was resumed as baseline data will be performed, as well as 
a comparison of efficacy between initial treatment and readministration to demonstrate 
the absence of significant differences (For details, see “Statistical Analysis Plan”). Data 
collected during readministration will not be included in analyses of data collected during 
initial treatment. 
The day of fixing maintenance dose is the day on which the initial maintenance dose was 
determined (Similarly, the day of fixing the maintenance dose for readministration is the 
day on which the initial maintenance dose was determined after the start of 
readministration). 
Serum sodium concentrations that were measured centrally will be used in these analyses. 
Efficacy will be comprehensively evaluated based on the following analysis and on 
individual subject data. 
7.4.1 
Primary Endpoint Analysis 
 
The primary endpoint is the percentage of subjects with normalized serum sodium 
concentration the day after the final IMP administration. 
The percentage of subjects with normalized serum concentration, defined as ≥135 mEq/L, 
on the day after final IMP administration will be calculated versus the number of subjects 
with serum sodium concentration of <135 mEq/L at baseline (predose on Day 1 of the 
treatment period). 
The number, percentage, and 95% CI of subjects with normalized serum sodium 
concentration on the day of fixing the maintenance dose and on the day after final IMP 
administration will be calculated. The number and percentage of subjects will also be 
calculated for each timepoint after start of IMP administration. 
7.4.2 
Secondary Endpoint Analyses 
 
7.4.2.1 
Change in Serum Sodium Concentration 
The number of subjects and the mean, standard deviation, minimum, median, and 
maximum values and 95% CI for measured values for serum sodium concentration and 
the change from baseline (predose on Day 1 of the treatment period) on the day of fixing 
the maintenance dose and on the day after final IMP administration will be calculated. 


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Descriptive statistics at each timepoint after start of IMP administration will also be 
calculated. 
7.4.2.2 
Time Course of Serum Sodium Concentration 
The individual time courses of measured values and changes from baseline for serum 
sodium concentration will be plotted. 
7.4.2.3 
Changes in Clinical Symptoms Associated With Hyponatremia 
Shift tables of the changes in clinical symptom gradings from baseline (pretreatment 
observation) to the day of fixing the maintenance dose and from baseline to the day after 
final IMP administration will be generated. Shift tables of the changes at each postdose 
timepoint will be generated in the same way. 
7.5 
Analyses of Demographic and Baseline Characteristics 
 
In the safety analysis set, the frequency distribution and descriptive statistics will be 
determined for the following subject characteristics. 
 Age 
 Gender 
 Height 
 Race 
 Ethnicity 
 Complications 
 Medical history 
 Etiology of SIADH 
 Duration of SIADH 
(Number of days from the latest date on which SIADH was diagnosed [or the date 
treatment of hyponatremia was judged to be needed] to the date of acquisition of 
informed consent) 
7.6 
Safety Analysis 
 
7.6.1 
Adverse Events 
 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidences of the following events will be 
summarized by treatment group: 
 Treatment-emergent AEs (TEAEs) 
 TEAEs by severity 
 TEAEs with an outcome of death 


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 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
TEAEs related to the IMP will be summarized, in the same manner as TEAEs. 
In addition to summarization of the data collected over the entire period of the trial, AE 
data will be summarized by time period (during the treatment period, from the day of the 
initial IMP administration to the day after the maintenance dose is determined, from 2 
days after the maintenance dose is determined to the day after the final IMP 
administration, and from 2 days after the final IMP administration to the follow-up 
examination). 
7.6.2 
Clinical Laboratory Tests 
For clinical laboratory tests other than the qualitative urinalysis, descriptive statistics of 
measured values and changes from baseline (predose on Day 1 of the treatment period) 
will be calculated at each timepoint. For the qualitative urinalysis parameter, shift tables 
at each timepoint, compared to baseline, will be prepared. For laboratory test parameters 
other than qualitative urinalysis, shift tables of subjects with values below, within, or 
above the normal range at each timepoint, compared to baseline, will be prepared. 
7.6.3 
Body Weight and Vital Signs 
 
For body weight and vital signs, descriptive statistics of measured values and changes 
from baseline (predose on Day 1 of the treatment period) will be calculated at each 
timepoint. 
7.6.4 
12-Lead Electrocardiography 
 
For 12-lead electrocardiographic parameters, the descriptive statistics of measured values 
and changes from baseline (pretreatment observation) will be calculated at each timepoint. 
The numbers and percentages of subjects who have a QTc interval of >450, >480, or 
>500 ms at any timepoint from baseline through the day after the final IMP 
administration will be calculated. In addition, the numbers and percentages of subjects 
who have a change in QTc interval from baseline of >30 and >60 ms at any timepoint 
from start of IMP administration through the day after the final IMP administration will 
be calculated. Shift tables for QTc interval interpretation (normal or abnormal) will be 
prepared from baseline through the day after the final IMP administration. 


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7.6.5 
Liver Function Tests 
 
The numbers and percentages of subjects who have a serum total bilirubin value of ≥2 
times the ULN, or an AST or ALT value of ≥3 times the ULN, at any timepoint after start 
of IMP administration will be calculated. 
 
 
8 
Management of Investigational Medicinal Products 
For full details on IMP management, see the tolvaptan investigator’s brochure and 
clinical operation manual. 
8.1 
Packaging and Labeling 
 
The IMP will be provided to the IMP manager by the sponsor or designated agent. The 
IMP will be supplied as package boxes. Each package box used in the treatment period 
will be labeled to clearly state “For clinical trial use only” as well as the protocol number, 
IMP name, quantity, Lot No., expiration date, storage conditions, subject ID, 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 may not provide the IMP to any patient who is 
not participating in this trial. 
The IMP will be stored at room temperature. 
The trial site staff will measure and record a temperature in the IMP storage area at least 
once each workday and maintain a temperature log. 
8.3 
Accountability 
 
The IMP manager must maintain an inventory record of IMP received, dispensed, 
administered, and returned. 
8.4 
Returns and Destruction 
 
Upon completion or termination of the trial, all unused IMP and partially used IMP must 
be returned to the sponsor or a designated agent. 
All IMP returned to the sponsor must be accompanied by appropriate documentation, and 
be identified by protocol number and trial site number on the outermost shipping 
container. Returned IMP should be in the original package boxes. The assigned trial 
monitor will facilitate the return of unused IMP and partially used IMP. 


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8.5 
Reporting of Product Quality Complaints 
 
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate, or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving: 
 Failure/malfunction of a product to meet any of its specifications 
 Incorrect or missing labeling 
 Packaging issues (eg, damaged, dirty, crushed, or missing product) 
 Blister defects (eg, missing, empty blisters) 
 Bottle defects (eg, under/over-fill, no safety seal) 
 Vial defects 
 Product defect (eg, odor, chipped, broken, embossing illegible) 
 Loss or theft of product 
 
8.5.1 
Eliciting and Reporting Product Quality Complaints 
 
The investigator, subinvestigator, or designee must record all PQCs identified through 
any means from the receipt of the IMP from the sponsor or sponsor’s designee, through 
and including reconciliation and up to destruction, including subject dosing. The 
investigator, subinvestigator, or designee must notify the sponsor by e-mail within 24 
hours of becoming aware of the PQC according to the procedure outlined below. 
 PQC_156-14-003@otsuka.jp 
The information specified in Section 8.5.2 will be sent to the above e-mail address. 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then report it to the sponsor according to the above- 
mentioned procedure. 
8.5.2 
Information Required for Reporting Purposes 
 
 Description of the compliant 
 Reporter identification (eg, subject, investigator or subinvestigator, trial site, etc.) 
 Reporter contact information (eg, address, phone number, e-mail address) 
 ID of material (product/compound name, coding) 
 Clinical protocol reference (number and/or trial name) 


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 Dosage form/strength (if known) 
 Pictures (if available) 
 Availability for return 
 
8.5.3 
Return Process 
 
During the report of the PQC, indicate whether the sample involved in the complaint is 
available for return. If the complaint sample is available for return, return it to the 
sponsor. 
Forwarding of the complaint sample to the sponsor for investigation must be documented 
in the site accountability record. 
8.5.4 
Assessment/Evaluation 
 
Assessment and evaluation of PQCs will be handled by the sponsor. 
 
 
9 
Records Management 
9.1 
Source Documents 
 
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, screening logs, and recorded data from automated instruments. 
Original source documents of the results of plasma drug concentration measurements will 
be retained by the bioanalytical laboratory. The sponsor will retain copies of all electronic 
file submitted by the bioanalytical laboratory. 
All source documents pertaining to this trial will be maintained by the trial sites and 
made available for direct inspection by authorized persons. The investigators/trial sites 
will permit trial-related monitoring, audits, IRB reviews, and regulatory inspection(s) by 
providing direct access to source data/documents by authorized persons as defined in the 
ICF. In all cases, subject confidentiality must be maintained in accordance with local 
regulatory requirements. 
9.2 
Data Collection 
 
During each subject’s visit to the trial site, the investigator or subinvestigator will keep a 
medical record to document all significant observations and findings. At minimum, the 
medical record will contain: 
 Documentation of the informed consent process, including any revised consents; 


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 Documentation of the investigator or subinvestigator’s decision to enroll the subject 
into the trial, the review of all inclusion/exclusion criteria prior to IMP administration, 
and confirmation of IMP administration commencement; 
 The date of the visit and the corresponding Visit or Day in the trial schedule; 
 General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs, and the 
investigator or subinvestigator’s assessment of causal relationship with the IMP must 
also be recorded; 
 Any changes in concomitant medications or dosages; 
 Medical activities provided; and, 
 The signature (or initials) and date of each investigator or subinvestigator who made 
an entry in the medical record (When using an electronic trial data system, a full audit 
trail should 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 or other source 
documents will be initialed and dated on the day the change is made by a trial site staff 
member who is authorized to make the change. Changes will be made by striking a single 
line through erroneous data (so as not to obliterate the original data), and clearly entering 
the correct data (eg, wrong data right data). If the reason for the change is not apparent, 
the investigator or subinvestigator will write a brief explanation for the change in the 
source documents. If an electronic trial data system is used, a full audit trail should be 
maintained. 
The information recorded on the medical record or other source documents should be 
directly entered in the sponsor’s electronic data capture system by the authorized trial site 
staff member. Changes to the data will be captured by an automatic audit trail. 
Results of clinical laboratory tests, urine osmolality, serum osmolality, urine sodium 
excretion, serum sodium concentration, and drug concentration measured by the central 
laboratory or bioanalytical laboratory will be directly transferred to the sponsor or 
contract research organization. Data that the sponsor will collect shall include: 
 Case report forms (data collected after the acquisition of informed consent) 
 Results of laboratory tests, urine osmolality, serum osmolality, etc. 
 Result table of the drug concentration (copy) 
 
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: Consolidated Guideline (E6) and as required by 


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applicable local regulations. The trial site will take measures to prevent the accidental or 
premature destruction of these documents. 
9.4 
Records Retention at the Trial Site 
 
The trial site should maintain all documents and records pertaining to the trial for the 
longer of the following 2 periods: In cases where the sponsor requires maintenance for a 
longer period, the trial site will discuss the storage period and method with the sponsor. 
 A period of at least 2 years after the date on which approval to market the IMP is 
obtained; or, a period of at least 3 years after the data on which the sponsor notifies 
the trial site that development of the IMP is discontinued or that the final report of 
this trial will not be submitted in the registration application for the IMP; 
 A period of at least 3 years after the trial is discontinued or completed. 
The trial site must not dispose of any records that are relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for the sponsor 
to collect such records. The trial site will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
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 GCP: Consolidated Guideline (E6), and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s monitors will visit the trial site during the trial, as well as communicate 
periodically via telephone, e-mail, and written communications. In addition, all 
investigators, subinvestigators, and trial site staff members will undergo initial and 
ongoing training for this particular trial, and this training will be clearly documented. 
10.2 
Auditing 
 
The sponsor’s Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to IMP supply, presence of essential documents, 
the informed consent process, and comparison of CRFs with source documents. The 
investigator should agree to participate with audits. 


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Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs. 
 
 
11 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP: Consolidated 
Guideline (E6), international ethical principles derived from the Declaration of Helsinki 
and Council for International Organizations of Medical Science guidelines, and 
applicable local laws and regulations. Each trial site will seek approval/favorable opinion 
by an IRB according to regional requirements, and provide that documentation to the 
sponsor. The IRB will evaluate the ethical, scientific, and medical appropriateness of the 
trial. Further, in preparing and handling CRFs, the investigator, subinvestigator and their 
staff members will take measures to ensure adequate care in protecting subject privacy. 
To this end, a subject number or subject ID will be used to identify each subject. 
Financial aspects, subject insurance and the publication policy for the trial results will be 
documented in the agreement between the sponsor and the trial site. 
 
 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy all of the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 
Subjects will be identified only by unique subject ID in CRFs. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials according to local regulations. 


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13 
Amendment Policy 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “nonsubstantial” amendments, investigators or 
subinvestigators will have to wait for IRB approval/favorable opinion of the amended 
protocol before implementing the change(s) or amendment(s). Administrative 
amendments are defined as changes that have no effects on the safety of subjects, conduct 
or management of the trial, trial design, or the quality or safety of IMP used in the trial. A 
protocol change intended to eliminate an apparent immediate hazard to subjects should be 
implemented immediately and reported to the IRB within the local applicable timeline. 
The sponsor will submit protocol amendments to the applicable regulatory agencies 
according to local applicable timelines. 
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to subjects, the 
currently approved ICFs and written information for subjects will be amended, as well. In 
such cases, after approval/favorable opinion of the new ICF and written information for 
subjects by the IRB, repeat written informed consent will be obtained from subjects 
enrolled in the trial before expecting continued participation and before the amendment- 
specified changes in the trial are implemented. 
 
 
14 
Publication Authorship Requirements 
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or, the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work, in ensuring that 
questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved. 


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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 subjects who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 
 
 
15 
References 
1 
Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia 
treatment guidelines 2007: expert panel recommendations. Am J Med. 
2007;120(11A): S1-S21. 
2 
Shoji M, Ota K, Kimura T. Treatment of SIADH. Clin Endocrinol. 1995;43: 1021-8. 
3 
Ishikawa S. SIADH. In: Orita Y (ed) Vasopressin and its Receptor Antagonism. Basic 
Principles and Clinical Applications. Osaka: Medical Review. 2011;141-9. 
4 
Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS. Tolvaptan, 
a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 
2006;355:2099-112. 
5 
Verbalis JG, Adler S, Schrier RW, Berl T, Zhao Q, Czerwiec FS. Efficacy and safety 
of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic 
hormone secretion. Eur J Endocrinol. 2011;164:725-32. 
6 
Peri A, Giuliani C. Management of euvolemic hyponatremia attributed to SIADH in 
the hospital setting. Minerva Endocrinol. 2014;39:33-41. 
7 
Laville M, Burst V, Peri A. Hyponatremia secondary to the syndrome of 
inappropriate secretion of antidiuretic hormone (SIADH): therapeutic decision- 
making in real-life cases. Clin Kidney J. 2013;6(Suppl 1):1-20. 
8 
Otsuka Pharmaceutical Europe Ltd. A multi-centre multi-national observational post- 
authorisation safety study to document the drug utilisation of Samsca® and to collect 
information on the safety of Samsca® when used in routine medical practice. Post 
Authorisation Safety Study (PASS) Report for Protocol 156-09-101, issued 5 Nov 
2014. 
9 
Otsuka Pharmaceutical Development & Commercialization, Inc. A phase 1b, 
multicenter, pilot, randomized, double-blind trial to determine the pharmacokinetics 
and pharmacodynamics of orally administered Tolvaptan 3.75, 7.5, and 15 mg tablets 
in subjects with syndrome of inappropriate antidiuretic hormone secretion. Clinical 
Study Report for Protocol 156-12-203, issued 26 Oct 2015. 
10 International Conference on Harmonization (ICH) [Internet]. E6: Good Clinical 
Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 Jun 1996; cited 
2014 Dec 5]. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E 
6/E6_R1_Guideline.pdf. 


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11 Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, Japanese 
translation, Japan Clinical Oncology Group (JCOG) (CTCAE v4.0-JCOG for short) 
[CTCAE v4.03/MedDRA v12.0 [MedDRA/J v19.0 in Japanese], March 10, 2016 
version] 
12 Ohta T, Waga S, Handa H, et al. New grading of level of consciousness in acute 
stage.In: Proceedings of the Third Conference of Surgical Treatment of Stroke. 
1975;61-9. 


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Appendix 1 
Diagnostic and Treatment Manual of the Hypersecretion of 
Vasopressin (SIADH), Revised in 2011 
 
 
Diagnostic and Treatment Manual for the Hypersecretion of Vasopressin (SIADH), 
Revised in 2011 
 
A. Diagnosis of Hypersecretion of Vasopressin (SIADH) 
I. Predominant symptoms 
1. Has no symptoms of dehydration 
2. May have symptoms of hyponatremia, such as malaise, appetite impaired, and 
consciousness disturbed 
 
II. Laboratory tests 
1. Hyponatremia: Serum sodium <135 mEq/L 
2. Plasma vasopressin: Measurable, when serum sodium is <135 mEq/L 
3. Blood hyposmosis: Plasma osmolality <280 mOsm/kg 
4. Hypersthenuria: Urine osmolality >300 mOsm/kg 
5. Persistent natriuresis: Urine sodium ≥20 mEq/L 
6. Normal renal function: Serum creatinine ≤1.2 mg/dL 
7. Normal adrenocortical function: Fasting morning serum cortisol ≥6 μg/dL 
 
III. Relevant findings 
1. The established diagnosis of the etiology of SIADH (Table 1) is helpful in the 
diagnosis of SIADH. 
2. Plasma renin activity is usually ≤5 ng/mL/h. 
3. Serum uric acid is usually ≤5 mg/dL. 
4. Fluid intake restriction improves hyponatremia, without aggravating dehydration. 
 
[Diagnostic Criteria] 
Patients with confirmed SIADH: Among the above criteria, I. 1 and II. 1 to 7 are met. 
 
[Differential diagnosis] 
The following conditions resulting in hyponatremia should be excluded. 
1. Hyponatremia with excess extracellular fluid volume: Heart failure, ascites 
associated with hepatic cirrhosis, nephrotic syndrome 
2. Hyponatremia with substantial sodium transudation: Renal sodium loss, diarrhoea, 
vomiting 


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Table 1. 
Etiology of Hypersecretion of Vasopressin (SIADH) 
 
1. Central nervous system disorders: 
Meningitis 
Trauma 
Subarachnoid hemorrhage 
Brain tumor 
Cerebral infarction/intracranial hemorrhage 
Guillain-Barre syndrome 
Encephalitis 
2. Lung diseases: 
Pneumonia 
Lung   tumors   (excluding   ectopic   vasopressin  producing 
tumors) 
Pulmonary tuberculosis 
Pulmonary aspergillosis 
Bronchial asthma 
Positive-pressure respiration 
3. Ectopic vasopressin producing tumors: 
Small cell lung cancer 
Pancreatic cancer 
4. Drugs: 
Vincristine 
Clofibrate 
Carbamazepine 
Amitriptyline 
Imipramine 
 
B. Treatment of Hypersecretion of Vasopressin (SIADH) 
Any of the following therapies (alone or combination) should be selected. 
1. Treat the underlying disease. 
2. Restrict daily fluid intake to 15 to 20 mL per kg of body weight. 
3. Administer salt (≥200 mEq/day) orally or parenterally. 
4. In patients who require acute treatment [eg, those with severe hyponatremia (≤120 
mEq/L) accompanied by a central nervous system disorder], administer 
furosemide as an intravenous dose of 10 to 20 mg, as needed, in combination with 
an amount of 3% saline equivalent to the urinary sodium excretion. To prevent 
central pontine myelinolysis, the daily increase in serum sodium should not 
exceed 10 mEq/L. 
5. In adult patients with SIADH secondary to ectopic vasopressin producing tumors 
who have displayed an inadequate response to other existing therapies, 
mozavaptan hydrochloride (one 30 mg tablet) may be orally administered once 
daily after a meal. If therapeutic effects are observed during the first 3 days, 
treatment may be continued for up to 7 days. 
6. Administer demeclocycline as an oral dose of 600 to 1200 mg/day. 
 
Health and Labour Sciences Research Grants, Research Project for Overcoming 
Intractable Diseases, Investigative Research Group for Diencephalon-Pituitary 
Dysfunction, Fiscal Year 2010 General Partial Research Report 
* Revised on 31 Mar 2011 


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Appendix 2 
Handling and Shipment of Pharmacokinetic Blood Samples 
Pharmacokinetic blood samples will be handled and shipped according to the procedure 
outlined below. 
1) Blood Sampling and Processing 
At each sampling timepoint, an approximately 2 mL blood sample must be taken by 
venipuncture using a heparin sodium-containing test tube, and the date and time of 
sampling will be recorded in the source document. The collected blood is to be mixed 
by slowly turning the test tube upside-down several times, and immediately (within 
45 minutes after sampling) centrifuged at approximately 1710 × g for approximately 
10 minutes at 4°C. The obtained plasma is to be separated equally and placed in 2 
sample stock tubes, to which sample labels containing the protocol number, subject 
identification number, timepoint of sampling, and other information are to be affixed. 
The plasma samples will be stored below −15°C. 
2) Shipment 
The trial site is to request for the central laboratory to collect samples. The central 
laboratory is to collect frozen samples with dry ice, store the samples below −15C°, 
and ship the samples with dry ice to the bioanalytical laboratory, when appropriate. 
3) Reporting and Recording of Results 
The bioanalytical laboratory is to measure the plasma concentrations of tolvaptan and 
its metabolites (DM-4103 and DM-4107) according to the procedures specified by the 
laboratory, and report the results to the sponsor. 
The investigator is to document blood sampling, as well as the date and time in the 
CRF. Since the results of measurements are to be reported directly to the sponsor by 
the bioanalytical laboratory, the entry of the results in the CRF is unnecessary. 


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Appendix 3 
Procedure for Readministration with the IMP 
If the serum sodium concentration has normalized (≥135 mEq/L) after start of IMP 
administration, the subject has no subjective symptoms associated with hyponatremia, 
and the investigator or subinvestigator judges that the serum sodium concentration is 
unlikely to decrease on withdrawal of the IMP, the treatment may be completed before 
the duration of treatment reaches 30 days. 
If hyponatremia recurs after treatment with the IMP has been completed before the 
duration of treatment reaches 30 days (except treatment discontinuations as specified in 
Section 3.8.3.1), and it is judged by the investigator or subinvestigator that 
readministration with the IMP is necessary, treatment may be resumed within 30 days 
after the initial IMP administration. 
Treatment with the IMP should be resumed according to the procedure outlined below. 
For matters that are not specified in this appendix, follow the requirements specified by 
the protocol. 
1) Trial Treatment 
 Dosage regimen 
The starting dose for readministration is 7.5 mg/day (one 7.5 mg tablet once daily), 
orally administered according to Section 3.2.1. 
The investigator or subinvestigator is to record the date on which resumption of the 
trial treatment is decided, and the reason(s) on the source document and CRF. 
 Dose titration 
After the start of readministration, the dose of the IMP will be increased as 
specified in Section 3.2.2, to determine a new maintenance dose for the subject. 
However, the treatment period will not be extended and will be completed when 30 
days have passed since the initial IMP administration even if this occurs before a 
new maintenance dose is determined. 
 Treatment period 
Treatment with the IMP will be continued until either of the following days, 
whichever comes first. 
 The day on which 30 days have passed since the initial IMP administration 
 The day on which the serum sodium concentration has normalized 
(≥135 mEq/L), the subject has no subjective symptoms associated with 
hyponatremia, and the investigator or subinvestigator judges that the serum 
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 Admission to and discharge from the trial site 
The subject is to be admitted to the trial site by the day before the start of 
retreatment. The subject may be switched to outpatient treatment at the judgement 
of the investigator or subinvestigator based on serum sodium concentration as 
specified in Section 3.2.5 on the day after the maintenance dose is determined or 
later. 
2) Readministration procedures 
 Day before the start of readministration 
The subject will be admitted to the trial site by the day before the start of 
readministration, at which time the investigator or subinvestigator will perform the 
procedures specified in Section 3.7.1.3 except daily urine volume, daily fluid 
intake, daily fluid balance, urinary sodium excretion, and urine osmolality. 
 Day 1 of readministration 
The investigator or subinvestigator is to perform the procedure specified in 
Section 3.7.1.4 except daily urine volume, daily fluid intake, daily fluid balance, 
urinary sodium excretion, and urine osmolality. Fluid intake must not be restricted 
within 24 hours after the IMP administration on Day 1 of readministration. 
 From Day 2 of readministration onward 
The investigator or subinvestigator is to perform the procedures specified in 
Section 3.7.1.5 to Section 3.7.1.13, and Section 3.7.1.15 to Section 3.7.1.18 except 
daily urine volume, daily fluid intake, daily fluid balance, urinary sodium excretion, 
and urine osmolality. 
 Day after the completion of readministration 
The investigator or subinvestigator is to perform the procedures specified in 
Section 3.7.1.14. 
 At Withdrawal 
The investigator or subinvestigator is to perform the procedures specified in 
Section 3.7.1.19. 
 Follow-up 
The subject is to visit the trial site 3 to 5 days and 7 to 10 days after the completion 
of readministration, at which time the investigator or subinvestigator is to perform 
the examinations and investigations specified in Section 3.7.1.20. 
 Assessment 
The requirements specified in Section 3.7.2, Section 3.7.3, and Section 3.7.4 
should be followed. 


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3) Withdrawal of individual subjects 
The requirements specified in Section 3.8.3 should be followed. 
4) Prohibited concomitant medications 
The requirements specified in Section 4.1 should be followed. 
5) Fluid intake restriction 
The requirements specified in Section 4.2 should be followed. Requirements 2) and 3) 
shall be read, as follows: 
2) Within 24 hours after the initial IMP administration on Day 1 of 
readministration 
Fluid intake must not be restricted. 
3) After the IMP administration on Day 2 of readministration onwards 
Setting the fluid intake volume from immediately before IMP administration 
on Day 1 of readministration to immediately before IMP administration on 
Day 2 of readministration as the upper limit of daily fluid intake, subjects will 
be instructed to restrict fluid intake. Fluid intake is the total volume of liquids 
taken as beverages (eg, juice, milk, tea), water, and transfusions, not including 
solid food-derived fluids. 
The investigator or subinvestigator should pay attention to an excessive 
increase in urine volume or rapid increase in serum sodium concentration. If 
thirst or dehydration, and other unfavorable symptoms develop, the 
investigator or subinvestigator should instruct the subject to take more fluids, 
regardless of the upper limit of daily fluid intake, to ensure the safety of the 
subject. 
6) Reporting of adverse events 
The requirements specified in Section 5 should be followed. 


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Appendix 4 
Protocol Amendments/Administrative Changes 
 
Amendment Number: 2 
 
Issue Date: 29 Mar 2017 
 
PURPOSE: 
Corrected entry omissions, etc. 
 
BACKGROUND: 
Since entry omissions were found, the protocol was modified. 
 
MODIFICATIONS TO THE PROTOCOL: 
 Measurement of urine sodium concentration (added) 
To Section 3.7.1.1 and Table 3.7-1, the measurement of urine sodium concentration 
during the screening period was added. 
 Urine sample processing (screening period) was added (corrected in association with 
the above change). 
To Section 3.7.4.2.6, “1) Urine sample processing (screening period)” was added. 
 Total volume of blood collected throughout the trial (description edited) 
The description regarding the total volume of blood collected in Section 3.7.3.2 was 
modified. 
 
ADDITIONAL RISK TO THE SUBJECTS: 
No additional risk will be imposed on the trial subjects. 


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Amendment Number: 3 
 
Issue Date: 23 Jun 2017 
 
PURPOSE: 
Corrected to uniformly confirm measured values for eligibility assessment and to edit 
descriptions 
 
BACKGROUND: 
Since the procedure for confirming the results of serum sodium concentration 
measurement was found to be inconsistent within the protocol, and the correction of a 
few descriptions was required, the protocol was modified. 
 
MODIFICATIONS TO THE PROTOCOL: 
 Section 3.2.1, Section 3.4.2, and Section 3.4.3 
The serum sodium concentrations used in the decisions regarding eligibility for 
inclusion, exclusion, dose escalation, maintenance dose, and switching to outpatient 
treatment were changed from “the serum sodium concentrations measured centrally” 
to “the serum sodium concentrations measured at each trial site.” 
 Protocol Synopsis, Subject Population 
The descriptions regarding the subject population were changed as follows: From 
“The sample size will be 16 subjects.” to “total of 16 subjects with a central 
measurement value for serum sodium concentration of <135 mEq/L at predose on 
Day 1 of the treatment period are to be treated with the investigational medicinal 
product (IMP).” and from “... of the above subjects treated with the IMP...” to “...of 
the above subjects...”. 
 Section 3.3.1 
The description, “The number of subjects treated with the IMP is to be 16.” was 
changed to “The trial population must include 16 subjects who are evaluable for the 
primary endpoint, the percentage of subjects with normalized serum sodium 
concentration (ie, subjects whose predose serum sodium concentration centrally 
measured on Day 1 is <135 mEq/L).” In addition, the description, “...of the above 
subjects treated with the IMP...” was changed to “...of the above subjects... .” 
[Subjects whose serum sodium concentration at baseline (predose on Day 1) is 
≥135 mEq/L will be excluded from the denominator data in calculating the 
percentage of subjects with normalized serum sodium concentration (the primary 
endpoint), according the inclusion criterion regarding serum sodium concentration. 


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The above descriptions were changed to result in the certain acquisition of 16 subjects 
who are evaluable for the primary endpoint, the percentage of subjects with 
normalized serum sodium concentration.] 
 Section 3.7.3.2 
The description of the volume of blood to be collected for the central measurement of 
serum sodium concentration, in addition to that for clinical laboratory tests was 
changed to “Blood samplings for the central measurement of serum sodium 
concentration for efficacy evaluation.” 
 Section 4.1 
The period of time during which the use of hypertonic saline is prohibited was 
changed from “from the pretreatment observation period until the completion of 
treatment” to “from the time informed consent is obtained until the completion of 
IMP.” 
 Section 7.3 
The description, “Missing data will not be imputed.” was changed to “Missing data 
on the day after the final IMP administration will be imputed using the last available 
data obtained by the day after the final IMP administration.” 
(A description about the handling of missing data on the day after the final IMP 
administration had been omitted.) 
 Section 7.4.1 and “Statistical Methods” of Protocol Synopsis 
The description, “in subjects whose serum sodium concentration is <135 mEq/L at 
baseline (predose on Day 1)” was added. 
(It was clearly stated that subjects whose serum sodium concentration at baseline is 
≥135 mEq/L are not included in the denominator data in calculation of the percentage 
of subjects with normalized serum sodium concentration.) 
 
ADDITIONAL RISK TO THE SUBJECTS: 
No additional risk will be imposed on the trial subjects. 


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Amendment Number: 4 
 
 
 
Issue Date: 14 Nov 2017 
 
PURPOSE: 
In consideration of the time required for measurement of the serum sodium concentration 
and determination of the maintenance dose, the allowable time window for the predose 
examination on or after Day 2 was redefined. 
 
BACKGROUND: 
Since some time is required from blood sampling for measurement of the serum sodium 
concentration to the IMP administration based on the measurement result, the 
descriptions regarding the allowable time window for the predose examination after Day 
2 of treatment period onwards, together with other inappropriate descriptions, were 
corrected. However, no changes were made to the descriptions on the days of plasma 
drug concentration measurement. 
 
MODIFICATIONS TO THE PROTOCOL: 
 Section 3.7.1.5 to Section 3.7.1.12 (Days 2 to 10, Day 14), Section 3.7.1.15 
(Procedure to be performed until the maintenance dose is determined), and 
Section 3.7.1.17 (When Determining the Possibility of Switching to Outpatient 
Treatment): common in all of these sections. 
1) Before IMP administration (21 to 24 hours after IMP administration on the day 
before) 
The timing of the predose examination was changed from “22 to 24 hours after IMP 
administration on the day before” to “21 to 24 hours after IMP administration on the 
day before.” 
 In addition, the following changes were made: the fax number on the title page was 
deleted; the description regarding the reporting of adverse events, “or maybe 
facsimile, if e-mail is not available” was changed to “by e-mail, as a rule”; and, the 
description regarding the reporting of IREs other than pregnancies was changed to 
“through the IRE form.” 
 
ADDITIONAL RISK TO THE SUBJECTS: 
No additional risk will be imposed on the trial subjects. 


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Amendment Number: 5 
 
Issue Date: 15 May 2018 
 
PURPOSE: 
The possibility that serum sodium concentration will drop rapidly upon the completion of 
treatment was considered. 
 
BACKGROUND: 
To address the possibility of a rapid drop of serum sodium concentration during the 
follow-up period, fluid intake restriction after the completion of treatment and 
measurement of the serum sodium concentration 3 to 5 days after the completion of 
treatment were specified. 
 
MODIFICATIONS TO THE PROTOCOL: 
 Section 3.1, Figure 3.1-1, Figure 3.1-2, and Section 3.7.2.1 
Descriptions were changed due to the additional measurement of serum sodium 
concentration. 
 Table 3.7-1 Schedule of Assessments 
The item field, “Fluid intake restriction” was added. 
 Table 3.7-1 Schedule of Assessments (Continued) 
To the follow-up, the two fields, “serum sodium concentration 3 to 5 days after 
completion” and “fluid intake restriction” were added. 
 Section 3.7.1.20 
The section title was changed to “Section 3.7.1.20 Follow-up,” and subsection 
“Section 3.7.1.20.1 Serum Sodium Concentration (3 to 5 Days After the Final IMP 
Administration)” was added. 
 Total volume of blood collected throughout the trial 
The total volume of blood collected in Section 3.7.3.2 was corrected (due to the 
additional measurement of serum sodium concentration 3 to 5 days after completion). 
 Section 4.2 
The subitem, “4) From the completion of the examination on the day after the final 
IMP administration to the completion of the follow-up examination” was added. 
 
ADDITIONAL RISK TO THE SUBJECTS: 
No additional risk will be imposed on the trial subjects. 


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Agreement 
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement. 
 
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, tolvaptan (OPC-41061), the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am aware that 
this protocol must be approved by the Institutional Review Board (IRB) responsible for such matters 
in the clinical trial facility where 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 on CRF by me and my staff will be 
utilized by the sponsor in various ways, such as for submission to governmental regulatory authorities 
and/or in combination with clinical data gathered from other research sites, whenever applicable. I 
agree to allow sponsor and designee monitors and auditors full access to all medical records at the 
research facility for subjects screened or enrolled in the trial. 
 
I agree to await IRB approval before implementation of any substantial amendments to this protocol. 
If, however, there is an immediate hazard to subjects, I will implement the amendment immediately, 
and provide the information to the IRB within the required local applicable timelines. Administrative 
changes to the protocol will be transmitted to the IRB for informational purposes only, if required by 
local regulations. 
 
I agree to provide all subjects with informed consent forms, as required by the applicable regulations 
and by ICH guidelines. I agree to report to the sponsor any adverse experiences in accordance with the 
terms of the sponsor's Clinical Trial Agreement and the relevant regional regulation(s) and 
guideline(s). I further agree to provide all required information regarding financial certification or 
disclosure to the sponsor for all investigators and subinvestigators in accordance with the terms of the 
relevant regional regulation(s). I understand that participation in the protocol involves a commitment 
to publish the data from this trial in a cooperative publication before publication of efficacy and safety 
results on an individual basis may occur, and I consent to be acknowledged in any such cooperative 
publications that result. 
 
 
 
 
Principal Investigator Print Name 
Trial Site 
 
 
 
Signature 
Date 
 
 
This agreement is digitally signed. The electronic signature page is attached to the agreement. 

SAP_000.pdf: 
 
 
 
STATISTICAL  ANALYSIS  PLAN 
 
 
 
A Multicenter, Uncontrolled, Open-label, Dose-titration Trial to 
Investigate the Efficacy and Safety of Tolvaptan Tablets in Patients 
With Hyponatremia in Syndrome of Inappropriate Antidiuretic 
Hormone Secretion (SIADH) 
 
 
 
 
                                                      NCT Number: 03048747 
                                                      PRT NO. ：156-14-003 
                                                      PRT Version Date: 19 Apr 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational Medicinal Product 
OPC-41061 
 
Protocol No. 156-14-003 
 
A Multicenter, Uncontrolled, Open-label, Dose-titration Trial to Investigate the Efficacy 
and Safety of Tolvaptan Tablets in Patients With Hyponatremia in Syndrome of 
Inappropriate Antidiuretic Hormone Secretion (SIADH) 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 19 Apr 2019 
Protocol Version 6 Date: 15 May 2018 
Date of Translation: 14 May 2019 
 
 
 
 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd. 


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Table of Contents 
Table of Contents ........................................................................................... 2 
List of Appendices .......................................................................................... 4 
List of Abbreviations and Definition of Terms ........................................... 5 
1 
Introduction .......................................................................................... 6 
2 
Trial Objectives ..................................................................................... 6 
3 
Trial Design ........................................................................................... 6 
3.1 
Type/Design of Trial ........................................................................................... 6 
3.2 
Trial Treatments .................................................................................................. 8 
3.3 
Trial Population ................................................................................................... 8 
3.4 
Handling of Timepoints ....................................................................................... 9 
4 
Sample Size ............................................................................................ 9 
5 
Statistical Analysis Datasets .............................................................. 10 
5.1 
Efficacy Analysis Set ........................................................................................ 10 
5.2 
Maintenance Dose-setting Set ........................................................................... 10 
5.3 
Safety Analysis Set ............................................................................................ 10 
5.4 
Pharmacokinetic Analysis Set ........................................................................... 10 
5.5 
Pharmacodynamic Analysis Set ........................................................................ 11 
5.6 
Handling of Missing Data ................................................................................. 11 
6 
Primary and Secondary Outcome Variables ................................... 11 
6.1 
Primary Outcome Variable ................................................................................ 11 
6.2 
Secondary Outcome Variables .......................................................................... 11 
7 
Disposition and Demographic Analysis ............................................ 11 
7.1 
Subject Disposition............................................................................................ 11 
7.2 
Demographic and Baseline Characteristics ....................................................... 12 
7.3 
Baseline Disease Evaluation ............................................................................. 12 
7.4 
Treatment Compliance ...................................................................................... 13 
7.5 
Prior and Concomitant Medications .................................................................. 13 
7.6 
Protocol Deviations ........................................................................................... 13 
8 
Efficacy Analysis ................................................................................. 13 
8.1 
Primary Efficacy Endpoint ................................................................................ 14 


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8.1.1 
Primary Efficacy Analysis .............................................................................. 14 
8.2 
Secondary Efficacy Endpoints .......................................................................... 14 
8.2.1 
Change in Serum Sodium Concentration ....................................................... 14 
8.2.2 
Time Course of Serum Sodium Concentration ............................................... 14 
8.2.3 
Changes in Clinical Symptoms Associated With Hyponatremia ................... 15 
8.3 
Subgroup Analyses and the Analysis by Dose .................................................. 15 
9 
Safety Analyses ................................................................................... 15 
9.1 
Extent of Exposure ............................................................................................ 15 
9.2 
Adverse Events .................................................................................................. 16 
9.3 
Clinical Laboratory Data ................................................................................... 16 
9.4 
Vital Sign Data .................................................................................................. 17 
9.5 
Electrocardiogram Data ..................................................................................... 17 
9.6 
Liver Function Tests .......................................................................................... 17 
10 
Pharmacokinetic Analyses ................................................................. 18 
11 
Pharmacodynamic Analyses .............................................................. 18 
12 
Pharmacogenomic Analyses .............................................................. 18 
13 
Interim Analysis .................................................................................. 18 
14 
Changes in the Planned Analyses ...................................................... 18 
 
 
 
 
 
 
 
 
 
 


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List of Appendices 
Appendix 1 
List of Summary Tables ................................................................ 20 
Appendix 2 
List of Subject Data Listings ......................................................... 42 


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List of Abbreviations and Definition of Terms 
 
Abbreviation 
Definition 
AE 
Adverse event 
IMP 
Investigational Medicinal Product 
MedDRA 
Medical Dictionary for Regulatory Activities 
SIADH 
Syndrome of inappropriate secretion of antidiuretic hormone 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
Descriptive statistics Number of subjects, mean, standard deviation, minimum, median, 
and maximum values 
Frequency 
distribution 
Number and percentage of subjects 


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1 
Introduction 
This statistical analysis plan documents the details of the statistical analysis methodology 
to be applied in the protocol of Trial 156-14-003. 
2 
Trial Objectives 
To determine the efficacy and safety of tolvaptan based on the change in serum sodium 
concentration following administration of tolvaptan oral tablets at 7.5 to 60 mg/day for up 
to 30 days in Japanese patients with hyponatremia in syndrome of inappropriate secretion 
of antidiuretic hormone (SIADH). 
3 
Trial Design 
(Refer to the corresponding sections in the trial protocol for the reference numbers 
indicated in this section.) 
3.1 
Type/Design of Trial 
This clinical trial is a multicenter, uncontrolled, open-label, dose-titration trial to 
investigate the efficacy and safety of tolvaptan administered for up to 30 days at a dose of 
7.5 to 60 mg/day, based on the change in serum sodium concentration in Japanese 
patients with hyponatremia secondary to SIADH. 
The trial consists of a screening period, pretreatment observation period, treatment period, 
and follow-up period. 
After written informed consent has been obtained, the investigator or subinvestigator will 
perform the screening examination to confirm the eligibility of the subject within 14 to 2 
days before start of investigational medicinal product (IMP) administration. The subject 
will be admitted to the trial site 2 days before start of IMP administration, at which 
eligibility for trial entry is confirmed during the pretreatment observation (the day before 
start of IMP administration) and predose on Day 1 of the treatment period. 
From Day 1, the IMP will be orally administered once daily after breakfast, and the 
specified observations, examinations, and investigations will be performed for the 
efficacy and safety evaluations. The starting dose of the IMP is 7.5 mg/day, which will be 
increased to 15 mg/day, followed by 30 mg/day then 60 mg/day on or after Day 2, 
according to Section 3.2.2, to determine the maintenance dose in each subject as specified 
in Section 3.2.3. Once the maintenance dose has been determined, the IMP will be 
administered continuously at that dose throughout the period defined by Section 3.2.4, as 
a rule. 


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If the subject becomes less responsive to the IMP due to exacerbation of the underlying 
disease or other causes, and the investigator or subinvestigator concludes that dose 
escalation is needed and this increase would raise no safety problems, the dose may be 
increased. When increasing the dose beyond the maintenance dose once it has been 
determined, the subject should be hospitalized at the trial site to determine a new 
maintenance dose according to Section 3.2.2. 
To prevent a too rapid increase in serum sodium concentration, fluid restriction should be 
avoided within 24 hours after IMP administration on Day 1 of the treatment period, based 
on safety considerations. From Day 2 of treatment period and onward, the investigator or 
subinvestigator will define the upper limit of daily fluid intake for the subject according 
to Section 4.2, and instruct the subject to take fluids depending on his/her condition. 
From the day after the maintenance dose has been determined and onward, a decision 
regarding switching the subject to outpatient treatment will be made as specified in 
Section 3.2.5. 
The maximum treatment duration is 30 days. If the serum sodium concentration has 
normalized (≥135 mEq/L), the subject has no subjective symptoms associated with 
hyponatremia, and the investigator or subinvestigator concludes that the serum sodium 
concentration is unlikely to decrease on withdrawal of the IMP, the treatment may be 
completed before the duration of treatment reaches 30 days. 
The subject should visit the trial site 7 to 10 days after the completion of IMP treatment 
to undergo the follow-up examination. Since serum sodium concentration is expected to 
decrease due to the withdrawal of treatment, serum sodium concentration will be 
measured 3 to 5 days after completion of IMP treatment. 
If hyponatremia recurs after treatment with the IMP has been completed before the 
duration of treatment reached 30 days (except treatment discontinuations as specified in 
Section 3.8.3.1), and it is judged by the investigator or subinvestigator that 
readministration with the IMP is necessary, treatment may be resumed within 30 days 
after the initial IMP administration. 
The trial participation period for each subject is from the date of signed informed consent 
to the trial completion date. 
Definition of trial completion date: 
The trial completion date is defined as the trial discontinuation date, or the date on which 
the follow-up examination is completed, whichever comes later (If 2 or more follow-up 


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examinations were performed, the date of the last examination will be taken as the trial 
completion date.) 
3.2 
Trial Treatments 
Subjects will take tolvaptan tablets once daily after breakfast with water. 
The starting dose of tolvaptan is 7.5 mg/day (one 7.5 mg tablet), which will be increased 
to 15 mg/day (one 15 mg tablet) on or after Day 2 of treatment period, followed by 30 
mg/day (one 30 mg tablet) and then 60 mg/day (two 30 mg tablets), as specified in 
Section 3.2.2 to determine the maintenance dose for each subject, according to Section 
3.2.3. Once the maintenance dose has been determined, the IMP will be administered 
continuously at that dose throughout the period defined by Section 3.2.4, as a rule. 
The dose may be reduced at any time during the treatment period, if any safety problem 
arises and the investigator or subinvestigator concludes that a dose reduction is necessary. 
Dose reduction should be performed as 1 dose level per day. 
If the subject becomes less responsive to the IMP due to exacerbation of underlying 
disease or other causes, and the investigator or subinvestigator concludes that dose 
escalation is needed and that this increase would raise no safety problems, the dose may 
be increased. When increasing the dose beyond the maintenance dose once it has been 
determined, the subject should be hospitalized at the trial site to determine a new 
maintenance dose according to Section 3.2.2. 
The serum sodium concentrations used to determine whether the subject meets the 
criteria for dose escalation, maintenance dose, and switching to outpatient treatment 
(Section 3.7.1.17) will be based on serum sodium concentrations measured at each trial 
site. 
3.3 
Trial Population 
In this trial, male and female Japanese patients with hyponatremia secondary to SIADH, 
aged from 20 to 85, inclusive at the time of consent are eligible. The trial population must 
include 16 subjects who are evaluable for the primary endpoint, the percentage of 
subjects with normalized serum sodium concentration (ie, subjects whose predose serum 
sodium concentration centrally measured on Day 1 is <135 mEq/L). Subject enrollment 
will be continued until a total of 16 evaluable subjects have been obtained. 
At least 50% (8/16) of the above subjects should comprise subjects with serum sodium 
concentration of <130 mEq/L at predose on Day 1 of the treatment period. In addition, 
the number of subjects with SIADH due to ectopic antidiuretic hormone-producing 


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tumors and the number of subjects with SIADH due to other causes should not be notably 
different. 
3.4 
Handling of Timepoints 
CRF Visit values at each timepoint (after the pretreatment observation period) will be 
used in summaries (but values at the time of discontinuation will not be used in 
summaries). Unscheduled Visit values will not be used for timepoint analyses. 
4 
Sample Size 
The target sample size was determined with respect to the percentage of subjects with a 
normalized serum sodium concentration (≥135 mEq/L) at the final administration of 
tolvaptan. 
Sample size determination was based on the results from patients with SIADH as the 
underlying disease of hyponatremia (“the SIADH subpopulation”) in the efficacy analysis 
sets of 2 overseas phase 3, placebo-controlled, randomized, double-blind trials in patients 
with hyponatremia due to SIADH and other causes (Trials 156-02-235 and 156-03-238, 
with an optional up-titration of 15, 30, and 60 mg for 30 days). To determine the sample 
size of this trial, a threshold percentage was set based on the results of the placebo group 
in the SIADH subpopulation of the overseas trials. Considering the distribution of the 
point estimates which are calculated based on multiple sample sizes, in the percentage of 
subjects with a normalized serum sodium concentration after the final IMP administration 
in the tolvaptan group, a sample size for which the probability of obtaining a point 
estimate exceeding the threshold percentage was kept at ≥80% was sought. In addition, 
since this trial intends to evaluate the efficacy and safety of tolvaptan in patients with 
SIADH due to a variety of etiologies, and to investigate the appropriateness of the dose- 
titration approach adopted as the dosage regimen, the various etiologies of SIADH and 
the expected number of subjects at each maintenance dose level were also taken into 
consideration in determination of the sample size. 
In the SIADH subpopulation of the 2 overseas phase 3 trials, the percentage of subjects 
with a normalized serum sodium concentration (Day 30, Last Observation Carried 
Forward) was 64.6% (31 of 48 subjects) in the tolvaptan group and 30.2% (16 of 53 
subjects) in the placebo group. Therefore, the threshold percentage was set at 44.3% (the 
upper limit of the exact 95% CI for the percentage of normalized subjects in the placebo 
group). When a binomial distribution with a parameter of 64.6% (the point estimate of 
the percentage of normalized subjects in the tolvaptan group) is assumed, the probability 


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that the expected point estimate of the percentage of normalized subjects will exceed the 
threshold percentage is kept at ≥80% with a sample size of ≥8 subjects. 
The underlying diseases of SIADH are diverse, and it is difficult to evaluate the efficacy 
of tolvaptan for each of all SIADH etiologies. Therefore, patients with SIADH will be 
divided into those with SIADH due to ectopic vasopressin producing tumors and those 
due to other etiologies to evaluate the efficacy of tolvaptan. Since the prevalence of these 
2 categories of patients is presumed to be nearly equivalent, a sample size of 16 subjects 
(8 subjects x 2) for the entire trial would enable an efficacy evaluation by SIADH 
etiology. 
In this trial, the following 4 maintenance dose levels have been established: 7.5, 15, 30, 
and 60 mg/day. A sample size for which the probability of obtaining at least 1 subject for 
each maintenance dose level is kept at ≥80% was calculated by applying the multinomial 
distribution. Since the proportion of subjects with each maintenance dose level in the trial 
is unpredictable, the subjects are assumed to be equally distributed to the 4 maintenance 
dose levels. By applying a polynomial distribution with a common parameter of 25% 
across the 4 maintenance dose levels, the sample size required to obtain at least 1 subject 
at each maintenance dose level with a ≥80% probability was 11 subjects. 
Based on the above results, the target sample size has been set as 16 subjects. 
5 
Statistical Analysis Datasets 
5.1 
Efficacy Analysis Set 
The efficacy analysis set consists of all subjects who received at least 1 dose of the IMP 
and have postdose serum sodium concentration data. 
5.2 
Maintenance Dose-setting Set 
Of the efficacy analysis set, the subpopulation comprised of the subjects for whom 
maintenance doses of the IMP were determined is defined as the maintenance dose- 
setting set. 
5.3 
Safety Analysis Set 
The safety analysis set consists of all subjects who received at least 1 dose of the IMP. 
5.4 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set consists of all subjects who received at least 1 dose of 
the IMP and have postdose drug concentration data. 


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5.5 
Pharmacodynamic Analysis Set 
 
The pharmacodynamic analysis set consists of all subjects who received at least 1 dose of 
the IMP and have postdose pharmacodynamic data. 
5.6 
Handling of Missing Data 
Missing data on the day after the final IMP administration will be imputed using the last 
available postdose data obtained by the day after the final administration. If multiple 
values are available on the day of trial discontinuation, the first obtained value will be 
used. 
6 
Primary and Secondary Outcome Variables 
6.1 
Primary Outcome Variable 
Percentage of subjects with normalized serum sodium concentration on the day after final 
IMP administration 
6.2 
Secondary Outcome Variables 
 
 Change in serum sodium concentration 
 Time course of serum sodium concentration 
 Changes in clinical symptoms associated with hyponatremia 
 
7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
 
For subjects from whom informed consent has been obtained (screened subjects), the 
numbers of subjects with acquired informed consent and of the IMP-treated subjects as 
well as the numbers and percentages of subjects who completed the IMP treatment and 
those who discontinued the IMP treatment (using the IMP-treated subjects as the 
denominator) will be summarized. The number and percentage of subjects who 
discontinued the IMP treatment after receiving IMP will be presented and summarized by 
reason for discontinuation. The number of subjects receiving IMP readministration and 
the numbers and percentages of subjects receiving IMP readministration who completed 
the treatment and those who discontinued the IMP treatment after receiving IMP 
readministration within the specified trial period will be summarized. 
For subjects receiving IMP administration, the number and percentage of subjects 
included in each statistical analysis set will be summarized. 


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7.2 
Demographic and Baseline Characteristics 
 
For the efficacy analysis set and safety analysis set, demographic and baseline 
characteristics will be summarized according to Table 7.2-1. The same analyses will also 
be performed by SIADH etiology (subjects with SIADH due to ectopic antidiuretic 
hormone-producing tumors/those due to other etiologies). 
 
Table 7.2-1 
Demographic and Baseline Characteristics 
Variable 
Timepoint 
Method 
Level 
Age (years) 
Informed consent 
acquisition 
Descriptive statistics 
- 
Frequency distribution 
20-29, 
30-39, 
40-49, 
50-59, 
60-69, 
70-79, 
80-85 
<65, 
≥65 
Sex 
- 
Frequency distribution 
Male, 
Female 
Height (cm) 
Screening 
Descriptive statistics 
- 
Body weight (kg) 
Screening 
Descriptive statistics 
- 
BMI (kg/m^2) 
Screening 
Descriptive statistics 
- 
Race 
- 
Frequency distribution 
Asian 
Ethnicity 
- 
Frequency distribution 
Not Hispanic or Latino 
Presence of 
complication 
Screening 
Frequency distribution 
Yes, 
No 
Presence of medical 
history 
Screening 
Frequency distribution 
Yes, 
No 
Etiology of SIADH 
Screening 
Frequency distribution 
Ectopic, 
Other 
Disease duration of 
SIADH* 
Screening 
Descriptive statistics 
- 
*Number of days from the date on which the latest diagnosis of SIADH was made (or the date on which hyponatremia 
requiring treatment was diagnosed) to the date of acquisition of informed consent. 
 
 
7.3 
Baseline Disease Evaluation 
For the efficacy analysis set and safety analysis set, each variable at baseline will be 
calculated. The same analyses will also be performed by SIADH etiology (subjects with 
SIADH due to ectopic antidiuretic hormone-producing tumors/those due to other 
etiologies). 


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Table 7.3-1 
Baseline Disease Evaluation 
Variable 
Method 
Level 
Serum sodium concentrations 
Descriptive statistics 
- 
Frequency distribution 
<130 mEq/L 
≥130 mEq/L 
Clinical symptoms associated 
with hyponatremia 
• Anorexia 
• Vomiting 
• Headache 
Frequency distribution 
Nothing, 
Grade 1, 
Grade 2, 
Grade 3, 
Unknown 
Clinical symptoms associated 
with hyponatremia 
• Consciousness disturbed 
Frequency distribution 
Nothing, 
1, 
2, 
3, 
10, 
20, 
30, 
100, 
200, 
300, 
Unknown 
Clinical symptoms associated 
with hyponatremia 
• Malaise 
Frequency distribution 
Nothing, 
Grade 1, 
Grade 2, 
Unknown 
 
7.4 
Treatment Compliance 
The frequency distribution of days with missed doses occurring between Day 1 of the 
treatment period and the completion or discontinuation of treatment will be determined in 
the efficacy and safety analysis sets, and subjects who are readministered with the IMP. 
7.5 
Prior and Concomitant Medications 
Prior and concomitant medications will not be tabulated in this trial. 
7.6 
Protocol Deviations 
Protocol deviations will not be tabulated in this trial. 
8 
Efficacy Analysis 
The following analyses will be performed in the efficacy analysis set. 
To evaluate the efficacy of tolvaptan in patients who achieved an appropriate 
maintenance dose, the same analyses will also be performed in the maintenance dose- 
setting set. 


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The day of fixing maintenance dose is the day on which the initial maintenance dose was 
determined (Similarly, the day of fixing the maintenance dose for readministration is the 
day on which the initial maintenance dose was determined after the start of 
readministration). 
Serum sodium concentrations that were measured centrally will be used in these analyses. 
Efficacy will be comprehensively evaluated based on the following analysis and on 
individual subject data. 
8.1 
Primary Efficacy Endpoint 
The primary endpoint is the percentage of subjects with normalized serum sodium 
concentration the day after the final IMP administration. 
The percentage of subjects with normalized serum concentration, defined as ≥135 mEq/L, 
on the day after final IMP administration will be calculated versus the number of subjects 
with serum sodium concentration of <135 mEq/L at baseline (predose on Day 1 of the 
treatment period). 
8.1.1 
Primary Efficacy Analysis 
The number, percentage, and 2-sided 95% CI (exact) of subjects with normalized serum 
sodium concentration on the day of fixing the maintenance dose and on the day after final 
IMP administration will be calculated. The number and percentage of subjects will also 
be calculated for each timepoint after start of IMP administration. 
 
 
8.2 
Secondary Efficacy Endpoints 
 
8.2.1 
Change in Serum Sodium Concentration 
Descriptive statistics (the number of subjects and the mean, standard deviation, minimum, 
median, and maximum values) and 2-sided 95% CI (based on the t distribution) for 
measured values for serum sodium concentration and the change from baseline (predose 
on Day 1 of the treatment period) on the day of fixing the maintenance dose and on the 
day after final IMP administration will be calculated. Descriptive statistics at each 
timepoint after start of IMP administration will also be calculated. 
8.2.2 
Time Course of Serum Sodium Concentration 
The individual time courses of measured values and changes from baseline for serum 
sodium concentration will be plotted with the horizontal axis representing timepoints 
(days of trial period). The individual time courses of measured values and changes from 


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baseline for serum sodium concentration will be plotted for the periods from the day of 
initial IMP administration to the follow-up visit and from the day of fixing the 
maintenance dose to the day after the final IMP administration. 
8.2.3 
Changes in Clinical Symptoms Associated With Hyponatremia 
Shift tables of the changes in clinical symptom gradings (anorexia, vomiting, headache, 
consciousness disturbed, and malaise) from baseline (pretreatment observation) to the 
day of fixing the maintenance dose and from baseline to the day after final IMP 
administration will be generated. Shift tables of consciousness disturbed will be 
generated for high categories (I, II, and III) and for low categories (1, 2, 3, 10, 20, 30, 100, 
200, and 300) from baseline (pretreatment observation) to the day of fixing the 
maintenance dose and from baseline to the day after final IMP administration. Shift tables 
of the changes at each postdose timepoint will be generated in the same way. 
8.3 
Subgroup Analyses and the Analysis by Dose 
Subgroup analyses by SIADH etiology (subjects with SIADH due to ectopic antidiuretic 
hormone-producing tumors/those due to other etiologies) and by serum sodium 
concentration (<130 mEq/L, ≥130 mEq/L) at predose on Day 1 of the treatment period 
will be performed for efficacy endpoints. 
For maintenance dose-setting set, a similar analysis will also be conducted by the dose 
administered at determination of the maintenance dose (7.5, 15, 30, and 60 mg) and the 
final dose. 
Except for the time course of serum sodium concentration, data obtained at fixing of 
maintenance dose and the day after the final IMP administration will be analyzed in the 
subgroup analyses and the analysis by dose administered at determination of the 
maintenance dose, and data obtained at the day after the final IMP administration will be 
analyzed in the analysis by the final dose. 
9 
Safety Analyses 
The following analyses will be performed in the safety analysis set. 
9.1 
Extent of Exposure 
 
The frequency distribution of subjects will be determined by the number of days of IMP 
administration (1 - 7 days, 8 - 14 days, 15 - 21 days, 22 - 29 days, and 30 days) during the 
period from Day 1 of the treatment period to the completion or discontinuation of 
treatment. In addition, the number of days of IMP administration will be summarized 
using descriptive statistics, and the frequency distribution of subjects will be determined 


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by maintenance dose, final dose, and highest dose. Similar analyses will be performed in 
subjects with the IMP readministration. 
9.2 
Adverse Events 
All adverse events (AEs) will be coded by system organ class (SOC) and preferred term 
(PT) (Medical Dictionary for Regulatory Activities [MedDRA]). The incidence of the 
following events will be summarized for all events, by SOC, and by PT. 
 Treatment-emergent AEs (TEAEs) 
 TEAEs by severity 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
If there are multiple occurrences of the same event in the same period in the same subject, 
the event with the highest severity will be selected. The above summaries will also be 
prepared for TEAEs potentially causally related to the IMP. 
In addition to summarization of the data collected over the entire period of the trial, AE 
data will be summarized by time period (“during the treatment period [including the day 
after the final IMP administration],” “from the day of the initial IMP administration to the 
day after the maintenance dose is determined,” “from 2 days after the maintenance dose 
is determined to the day after the final IMP administration,” and “from 2 days after the 
final IMP administration to the follow-up examination”). Adverse events occurring from 
the day of the initial IMP administration to the day after the final IMP administration in 
subjects whose maintenance dose has not been determined will be classified in the time 
period “from the day of the initial IMP administration to the day after the maintenance 
dose is determined.” 
9.3 
Clinical Laboratory Data 
For clinical laboratory tests other than the qualitative urinalysis, descriptive statistics of 
measured values and changes from baseline (predose on Day 1 of the treatment period) 
will be calculated on the day after the final IMP administration and at each timepoint. For 
the qualitative urinalysis parameters, shift tables of the day after the final IMP 
administration and at each timepoint, compared to baseline, will be prepared. For 
laboratory test parameters other than qualitative urinalysis, shift tables of subjects with 
values below, within, or above the normal range of the bioanalytical laboratory on the 
day after the final IMP administration and at each timepoint, compared to baseline, will 
be prepared. 


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9.4 
Vital Sign Data 
 
For body weight and vital signs, descriptive statistics of measured values and changes 
from baseline (predose on Day 1 of the treatment period) will be calculated on the day 
after final IMP administration and at each timepoint. 
9.5 
Electrocardiogram Data 
For 12-lead electrocardiographic parameters and QTcF (rounded to the nearest integer 
data in msec, QTcF = QT/RR0.33, RR = 60/heart rate), measured values and changes from 
baseline (pretreatment observation period) on the day after final IMP administration and 
at each timepoint will be summarized using descriptive statistics. 
The numbers and percentages of subjects who have a QTcF interval of >450, >480, or 
>500 ms at any postdose timepoint from start of IMP administration through the day after 
the final IMP administration will be calculated. In addition, the numbers and percentages 
of subjects who have a change in QTcF interval from baseline of >30 and >60 ms at any 
postdose timepoint from start of IMP administration through the day after the final IMP 
administration will be calculated. The numbers and percentages at baseline and each 
postdose timepoint will be calculated in the same way. 
Shift tables for QTcF interval interpretation (normal or abnormal) will be prepared from 
baseline through each timepoint and the day after the final IMP administration. 
9.6 
Liver Function Tests 
The numbers and percentages of subjects who have a serum total bilirubin value of ≥2 
times the upper limit of normal (ULN), and AST or ALT value of ≥3 times the ULN, at 
any postdose timepoint will be calculated. 
Subgroup Analyses and the Analysis by Dose 
Subgroup analyses by SIADH etiology (subjects with SIADH due to ectopic antidiuretic 
hormone-producing tumors/those due to other etiologies) and by serum sodium 
concentration (<130 mEq/L, ≥130 mEq/L) at predose on Day 1 of the treatment period 
will be performed for safety endpoints. 
For subjects in the safety analysis set for whom maintenance doses of the IMP were 
determined, a similar analysis will also be conducted by the dose administered at 
determination of the maintenance dose (7.5, 15, 30, and 60 mg) and the final dose. 
Except for adverse events and liver function tests, data obtained at the day after the final 
IMP administration will be analyzed in the subgroup analyses and the analysis by dose 
administered. 


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10 
Pharmacokinetic Analyses 
In the pharmacokinetic analysis set, the plasma concentrations of tolvaptan and its 
metabolites, DM-4103 and DM-4107 on Day 21 and the day after the final IMP 
administration will be adjusted for the dose administered immediately before each 
timepoint to calculate descriptive statistics (n, mean, standard deviation, minimum, 
median, and maximum) by timepoint and by compound. 
11 
Pharmacodynamic Analyses 
Pharmacodynamic analyses will be performed in the pharmacodynamic analysis set. For 
the parameters below, measured values and changes from baseline (at predose on Day 1 
of the treatment period for serum osmolality and plasma AVP concentration or at 24 
hours predose on Day 1 of the treatment period for other parameters) at each timepoint 
will be summarized using descriptive statistics. 
 Daily urine volume 
 Daily fluid intake 
 Daily fluid balance 
 Serum osmolality 
 Urine osmolality 
 Daily urinary sodium excretion 
 Plasma AVP concentration 
 
12 
Pharmacogenomic Analyses 
Pharmacogenomic analyses will not be tabulated in this trial. 
13 
Interim Analysis 
No interim analysis will be performed in this trial. 
14 Changes in the Planned Analyses 
 To correct an entry omission in Section 7.3 of the Trial Protocol, the description “will 
be imputed using the last available data obtained by the day after the final 
administration” to “will be imputed using the last available postdose data obtained by 
the day after the final administration.” 
 Section 7.4 of the Trial Protocol specified as follows: “In patients receiving 
readministration with the IMP, similar analyses using the data immediately before 
treatment was resumed as baseline data will performed, as well as a comparison of 
efficacy between initial treatment and readministration to demonstrate the absence of 


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significant differences (For details, see the “Statistical Analysis Plan”).” However, 
these analyses were cancelled and limited to the individual assessment, because only 
1 subject received readministration of the IMP. 
 To correct an error in writing in Section 7.6.1 of the Trial Protocol, the description 
regarding the summarization by time period “(during the treatment period, from the 
day of the initial IMP administration to the day after the maintenance dose is 
determined, from 2 days after the maintenance dose is determined to the day after the 
final IMP administration, and from 2 days after the final IMP administration to the 
follow-up examination)” was changed to “(“during the treatment period [including 
the day after the final IMP administration],” “from the day of the initial IMP 
administration to the day after the maintenance dose is determined”, and “from 2 days 
after the maintenance dose is determined to the day after the final IMP 
administration,” and “from 2 days after the final IMP administration to the follow-up 
examination”).” 
 To correct an error in writing in Section 7.6.5 of the Trial Protocol the description 
“The numbers and percentages of subjects who have a serum total bilirubin value of 
≥2 times the ULN, or an AST or ALT value of ≥3 times the ULN, at any timepoint 
after start of IMP administration will be calculated.” was changed to “The numbers 
and percentages of subjects who have a serum total bilirubin value of ≥2 times the 
upper limit of normal (ULN), and an AST or ALT value of ≥3 times the ULN, at any 
postdose timepoint will be calculated.” 
 To correct an error in writing in Section 6.1 of the Trial Protocol the description “on 
Day 21, at discontinuation of treatment, and on the day after the final IMP 
administration” was changed to “on Day 21 and the day after the final IMP 
administration.” 
 
References 
None. 


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Appendix 1 
List of Summary Tables 
CT-1.1 
Subject Disposition (Screened Subjects) 
CT-1.2 
Analysis Set (IMP Administered Subjects) 
CT-2 
Reasons for Discontinuation (IMP Administered Subjects) 
CT-3.1.1 
Demographic and Baseline Characteristics (Safety Analysis Set) 
CT-3.1.2 
Demographic and Baseline Characteristics (Efficacy Analysis Set) 
CT-3.1.3 
Demographic and Baseline Characteristics by Underlying Disease Leading 
to SIADH (Safety Analysis Set) 
CT-3.1.4 
Demographic and Baseline Characteristics by Underlying Disease Leading 
to SIADH (Efficacy Analysis Set) 
CT-3.2.1 
Baseline Disease Evaluations (Safety Analysis Set) 
CT-3.2.2 
Baseline Disease Evaluations (Efficacy Analysis Set) 
CT-3.2.3 
Baseline Disease Evaluations by Underlying Disease Leading to SIADH 
(Safety Analysis Set) 
CT-3.2.4 
Baseline Disease Evaluations by Underlying Disease Leading to SIADH 
(Efficacy Analysis Set) 
CT-5.1 
Percentage of Subjects with Normalized Serum Sodium Concentration for 
Efficacy Analysis Set 
CT-5.2 
Percentage of Subjects with Normalized Serum Sodium Concentration for 
Maintenance Dose-setting Set 
CT-5.3 
Percentage of Subjects with Normalized Serum Sodium Concentration by 
Underlying Disease Leading to SIADH for Efficacy Analysis Set 
CT-5.4 
Percentage of Subjects with Normalized Serum Sodium Concentration by 
Underlying Disease Leading to SIADH for Maintenance Dose-setting Set 
CT-5.5 
Percentage of Subjects with Normalized Serum Sodium Concentration by 
Baseline Sodium Level for Efficacy Analysis Set 
CT-5.6 
Percentage of Subjects with Normalized Serum Sodium Concentration by 
Baseline Sodium Level for Maintenance Dose-setting Set 
CT-5.7 
Percentage of Subjects with Normalized Serum Sodium Concentration by 
Maintenance Dose for Maintenance Dose-setting Set 


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CT-5.8 
Percentage of Subjects with Normalized Serum Sodium Concentration by 
Final Dose for Maintenance Dose-setting Set 
CT-6.1.1 
Descriptive Statistics for Change from Baseline in Serum Sodium 
Concentration for Efficacy Analysis Set 
CT-6.1.2 
Descriptive Statistics for Change from Baseline in Serum Sodium 
Concentration for Maintenance Dose-setting Set 
CT-6.1.3 
Descriptive Statistics for Change from Baseline in Serum Sodium 
Concentration by Underlying Disease Leading to SIADH for Efficacy 
Analysis Set 
CT-6.1.4 
Descriptive Statistics for Change from Baseline in Serum Sodium 
Concentration by Underlying Disease Leading to SIADH for Maintenance 
Dose-setting Set 
CT-6.1.5 
Descriptive Statistics for Change from Baseline in Serum Sodium 
Concentration by Baseline Sodium Level for Efficacy Analysis Set 
CT-6.1.6 
Descriptive Statistics for Change from Baseline in Serum Sodium 
Concentration by Baseline Sodium Level for Maintenance Dose-setting Set 
CT-6.1.7 
Descriptive Statistics for Change from Baseline in Serum Sodium 
Concentration by Maintenance Dose for Maintenance Dose-setting Set 
CT-6.1.8 
Descriptive Statistics for Change from Baseline in Serum Sodium 
Concentration by Final Dose for Maintenance Dose-setting Set 
CT-6.2.1 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia for Efficacy Analysis Set (Other Than Consiousness 
Disorder) 
CT-6.2.2 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia for Maintenance Dose-setting Set (Other Than Consiousness 
Disorder) 
CT-6.2.3 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Underlying Disease Leading to SIADH for Efficacy 
Analysis Set (Other Than Consiousness Disorder) 
CT-6.2.4 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Underlying Disease Leading to SIADH for Maintenance 
Dose-setting Set (Other Than Consiousness Disorder) 


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CT-6.2.5 
Shift Tables of the Changes in Clinical Symptom Associated with 
 
 
Hyponatremia by baseline sodium level for Efficacy Analysis Set (Other 
Than Consiousness Disorder) 
CT-6.2.6 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by baseline sodium level for Maintenance Dose-setting Set 
(Other Than Consiousness Disorder) 
CT-6.2.7 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Maintenance Dose for Maintenance Dose-setting Set 
(Other Than Consiousness Disorder) 
CT-6.2.8 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Final Dose for Maintenance Dose-setting Set (Other Than 
Consiousness Disorder) 
CT-6.3.1 Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia for Efficacy Analysis Set (Consiousness Disorder - 
Mainscale) 
CT-6.3.2 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia for Maintenance Dose-setting Set (Consiousness Disorder - 
Mainscale) 
CT-6.3.3 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Underlying Disease Leading to SIADH for Efficacy 
Analysis Set (Consiousness Disorder - Mainscale) 
CT-6.3.4 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Underlying Disease Leading to SIADH for Maintenance 
Dose-setting Set (Consiousness Disorder - Mainscale) 
CT-6.3.5 Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by baseline sodium level for Efficacy Analysis Set 
(Consiousness Disorder - Mainscale) 
CT-6.3.6 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by baseline sodium level for Maintenance Dose-setting Set 
(Consiousness Disorder - Mainscale) 
CT-6.3.7 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Maintenance Dose for Maintenance Dose-setting Set 
(Consiousness Disorder - Mainscale) 


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CT-6.3.8 
Shift Tables of the Changes in Clinical Symptom Associated with 
 
 
Hyponatremia by Final Dose for Maintenance Dose-setting Set 
(Consiousness Disorder - Mainscale) 
CT-6.4.1 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia for Efficacy Analysis Set (Consiousness Disorder - Subscale) 
CT-6.4.2 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia for Maintenance Dose-setting Set (Consiousness Disorder - 
Subscale) 
CT-6.4.3 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Underlying Disease Leading to SIADH for Efficacy 
Analysis Set (Consiousness Disorder - Subscale) 
CT-6.4.4 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Underlying Disease Leading to SIADH for Maintenance 
Dose-setting Set (Consiousness Disorder - Subscale) 
CT-6.4.5 Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by baseline sodium level for Efficacy Analysis Set 
(Consiousness Disorder - Subscale) 
CT-6.4.6 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by baseline sodium level for Maintenance Dose-setting Set 
(Consiousness Disorder - Subscale) 
CT-6.4.7 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Maintenance Dose for Maintenance Dose-setting Set 
(Consiousness Disorder - Subscale) 
CT-6.4.8 
Shift Tables of the Changes in Clinical Symptom Associated with 
Hyponatremia by Final Dose for Maintenance Dose-setting Set 
(Consiousness Disorder - Subscale) 
CT-7.1 
Extent of Exposure to Investigational Medicinal Product (Safety Analysis 
Set) 
CT-7.2.1 
Treatment Compliance (Safety Analysis Set) 
CT-7.2.2 
Treatment Compliance (Efficacy Analysis Set) 
CT-8.1 
Overall Summary of Adverse Events (Safety Analysis Set) 


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CT-8.2.1.1 Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.2.1.2 Incidences of Treatment-emergent Adverse Events occurring in >= 2 
subjects by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set) 
CT-8.2.2 
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Underlying Disease Leading to SIADH 
(Safety Analysis Set) 
CT-8.2.3 
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Baseline Sodium Level (Safety 
Analysis Set) 
CT-8.2.4 
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Maintenance Dose (Subjects in The 
Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-8.2.5 
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Final Dose (Subjects in The Safety 
Analysis Set for whom Maintenance Doses of The IMP were Determined) 
CT-8.3.1 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.3.2 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Underlying 
Disease Leading to SIADH (Safety Analysis Set) 
CT-8.3.3 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Baseline Sodium 
Level (Safety Analysis Set) 
CT-8.3.4 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Maintenance Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 
CT-8.3.5 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Final Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 


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CT-8.4.1 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.4.2 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term by Underlying Disease Leading to 
SIADH (Safety Analysis Set) 
CT-8.4.3 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term by Baseline Sodium Level (Safety 
Analysis Set) 
CT-8.4.4 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term by Maintenance Dose (Subjects in 
The Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-8.4.5 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term by Final Dose (Subjects in The 
Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-8.5.1 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by Severity by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set) 
CT-8.5.2 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by Severity by MedDRA System Organ Class and Preferred Term by 
Underlying Disease Leading to SIADH (Safety Analysis Set) 
CT-8.5.3 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by Severity by MedDRA System Organ Class and Preferred Term by 
Baseline Sodium Level (Safety Analysis Set) 
CT-8.5.4 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by Severity by MedDRA System Organ Class and Preferred Term by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-8.5.5   Incidences of Potentially Drug-related Treatment-emergent Adverse Events by 
Severity by MedDRA System Organ Class and Preferred Term by Final 
Dose (Subjects in The Safety Analysis Set for whom Maintenance Doses of 
The IMP were Determined) 


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CT-8.7.1 
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Period (Safety Analysis Set) 
CT-8.7.2 
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Period by Underlying Disease Leading 
to SIADH (Safety Analysis Set) 
CT-8.7.3 
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Period by Baseline Sodium Level 
(Safety Analysis Set) 
CT-8.7.4 
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Period by Maintenance Dose (Subjects 
in The Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-8.7.5 
Incidences of Treatment-emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Period by Final Dose (Subjects in The 
Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-8.8.1 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Period (Safety 
Analysis Set) 
CT-8.8.2 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Period by 
Underlying Disease Leading to SIADH (Safety Analysis Set) 
CT-8.8.3 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Period by Baseline 
Sodium Level (Safety Analysis Set) 
CT-8.8.4 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Period by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-8.8.5 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Period by Final 
Dose (Subjects in The Safety Analysis Set for whom Maintenance Doses of 
The IMP were Determined) 


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CT-8.9.1 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term by Period (Safety Analysis Set) 
CT-8.9.2 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term by Period by Underlying Disease 
Leading to SIADH (Safety Analysis Set) 
CT-8.9.3 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term by Period by Baseline Sodium 
Level (Safety Analysis Set) 
CT-8.9.4 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term by Period by Maintenance Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 
CT-8.9.5 
Incidences of Treatment-emergent Adverse Events by Severity by MedDRA 
System Organ Class and Preferred Term by Period by Final Dose (Subjects 
in The Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-8.10.1 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by Severity by MedDRA System Organ Class and Preferred Term by Period 
(Safety Analysis Set) 
CT-8.10.2 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by Severity by MedDRA System Organ Class and Preferred Term by Period 
by Underlying Disease Leading to SIADH (Safety Analysis Set) 
CT-8.10.3 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by Severity by MedDRA System Organ Class and Preferred Term by Period 
by Baseline Sodium Level (Safety Analysis Set) 
CT-8.10.4 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by Severity by MedDRA System Organ Class and Preferred Term by Period 
by Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-8.10.5 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
by Severity by MedDRA System Organ Class and Preferred Term by Period 
by Final Dose (Subjects in The Safety Analysis Set for whom Maintenance 
Doses of The IMP were Determined) 


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CT-9.1.1 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set) 
CT-9.1.2 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term by Underlying 
Disease Leading to SIADH (Safety Analysis Set) 
CT-9.1.3 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term by Baseline 
Sodium Level (Safety Analysis Set) 
CT-9.1.4 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-9.1.5 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term by Final Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 
CT-9.2.1 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term (Safety Analysis Set) 
CT-9.2.2 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term by Underlying Disease Leading to SIADH (Safety Analysis Set) 
CT-9.2.3 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term by Baseline Sodium Level (Safety Analysis Set) 
CT-9.2.4 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term by Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-9.2.5 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term by Final Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 


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CT-9.3.1 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term (Safety Analysis Set) 
CT-9.3.2 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Underlying Disease Leading to 
SIADH (Safety Analysis Set) 
CT-9.3.3 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Baseline Sodium Level (Safety 
Analysis Set) 
CT-9.3.4 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Maintenance Dose (Subjects in 
The Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-9.3.5 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Final Dose (Subjects in The 
Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-9.4.1 
Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set) 
CT-9.4.2 Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by Underlying 
Disease Leading to SIADH (Safety Analysis Set) 
CT-9.4.3 
Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by Baseline 
Sodium Level (Safety Analysis Set) 
CT-9.4.4 
Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-9.4.5 
Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by Final Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 


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CT-9.5.1 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set) 
CT-9.5.2 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term by Underlying Disease 
Leading to SIADH (Safety Analysis Set) 
CT-9.5.3 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term by Baseline Sodium 
Level (Safety Analysis Set) 
CT-9.5.4 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term by Maintenance Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 
CT-9.5.5 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term by Final Dose (Subjects 
in The Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-9.6.1 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-9.6.2 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term by 
Underlying Disease Leading to SIADH (Safety Analysis Set) 
CT-9.6.3 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term by 
Baseline Sodium Level (Safety Analysis Set) 


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CT-9.6.4 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
 
 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-9.6.5 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term by 
Final Dose (Subjects in The Safety Analysis Set for whom Maintenance 
Doses of The IMP were Determined) 
CT-9.7.1 Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term by Period 
(Safety Analysis Set) 
CT-9.7.2 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term by Period by 
Underlying Disease Leading to SIADH (Safety Analysis Set) 
CT-9.7.3 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term by Period by 
Baseline Sodium Level (Safety Analysis Set) 
CT-9.7.4 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term by Period by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-9.7.5 
Incidences of Treatment-emergent Adverse Events with an outcome of 
death by MedDRA System Organ Class and Preferred Term by Period by 
Final Dose (Subjects in The Safety Analysis Set for whom Maintenance 
Doses of The IMP were Determined) 
CT-9.8.1 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term by Period (Safety Analysis Set) 
CT-9.8.2 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term by Period by Underlying Disease Leading to SIADH (Safety Analysis 
Set) 


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CT-9.8.3 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
 
 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term by Period by Baseline Sodium Level (Safety Analysis Set) 
CT-9.8.4 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term by Period by Maintenance Dose (Subjects in The Safety Analysis Set 
for whom Maintenance Doses of The IMP were Determined) 
CT-9.8.5 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
with an outcome of death by MedDRA System Organ Class and Preferred 
Term by Period by Final Dose (Subjects in The Safety Analysis Set for 
whom Maintenance Doses of The IMP were Determined) 
CT-9.9.1 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Period (Safety Analysis Set) 
CT-9.9.2 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Period by Underlying Disease 
Leading to SIADH (Safety Analysis Set) 
CT-9.9.3 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Period by Baseline Sodium 
Level (Safety Analysis Set) 
CT-9.9.4 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Period by Maintenance Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 
CT-9.9.5 
Incidences of Serious Treatment-emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Period by Final Dose (Subjects 
in The Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-9.10.1 
Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by Period 
(Safety Analysis Set) 
CT-9.10.2 
Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by Period by 
Underlying Disease Leading to SIADH (Safety Analysis Set) 


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CT-9.10.3 
Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by Period by 
Baseline Sodium Level (Safety Analysis Set) 
CT-9.10.4 
Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by Period by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-9.10.5 
Incidences of Potentially Drug-related Serious Treatment-emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by Period by 
Final Dose (Subjects in The Safety Analysis Set for whom Maintenance 
Doses of The IMP were Determined) 
CT-9.11.1 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term by Period (Safety 
Analysis Set) 
CT-9.11.2 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term by Period by Underlying 
Disease Leading to SIADH (Safety Analysis Set) 
CT-9.11.3 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term by Period by Baseline 
Sodium Level (Safety Analysis Set) 
CT-9.11.4 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term by Period by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-9.11.5 
Incidences of Treatment-emergent Adverse Events Leading to 
Discontinuation of Investigational Medicinal Product Administration by 
MedDRA System Organ Class and Preferred Term by Period by Final Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 


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CT-9.12.1 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term by 
Period (Safety Analysis Set) 
CT-9.12.2 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term by 
Period by Underlying Disease Leading to SIADH (Safety Analysis Set) 
CT-9.12.3 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term by 
Period by Baseline Sodium Level (Safety Analysis Set) 
CT-9.12.4 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term by 
Period by Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-9.12.5 
Incidences of Potentially Drug-related Treatment-emergent Adverse Events 
Leading to Discontinuation of Investigational Medicinal Product 
Administration by MedDRA System Organ Class and Preferred Term by 
Period by Final Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-9.13 
Listing of Deaths (Safety Analysis Set) 
CT-9.14 
Listing of Serious Adverse Events Other Than Death (Safety Analysis Set) 
CT-9.15 
Listing of Adverse Events Leading to Discontinuation of Investigational 
Medicinal Product Administration (Safety Analysis Set) 
CT-10.1.1 
Mean Change from Baseline in Clinical Laboratory Test Results (Serum 
Chemistry, Hematology, Urinalysis) (Safety Analysis Set) 
CT-10.1.2 
Mean Change from Baseline in Clinical Laboratory Test Results (Serum 
Chemistry, Hematology, Urinalysis) by Underlying Disease Leading to 
SIADH (Safety Analysis Set) 
CT-10.1.3 
Mean Change from Baseline in Clinical Laboratory Test Results (Serum 
Chemistry, Hematology, Urinalysis) by Baseline Sodium Level (Safety 
Analysis Set) 


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CT-10.1.4 
Mean Change from Baseline in Clinical Laboratory Test Results (Serum 
Chemistry, Hematology, Urinalysis) by Maintenance Dose (Subjects in The 
Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-10.1.5 
Mean Change from Baseline in Clinical Laboratory Test Results (Serum 
Chemistry, Hematology, Urinalysis) by Final Dose (Subjects in The Safety 
Analysis Set for whom Maintenance Doses of The IMP were Determined) 
CT-10.2.1 
Shift Tables of Clinical Laboratory Test Results (Qualitative Urinalysis) 
(Safety Analysis Set) 
CT-10.2.2 
Shift Tables of Clinical Laboratory Test Results (Qualitative Urinalysis) by 
Underlying Disease Leading to SIADH (Safety Analysis Set) 
CT-10.2.3 
Shift Tables of Clinical Laboratory Test Results (Qualitative Urinalysis) by 
Baseline Sodium Level (Safety Analysis Set) 
CT-10.2.4 
Shift Tables of Clinical Laboratory Test Results (Qualitative Urinalysis) by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-10.2.5 
Shift Tables of Clinical Laboratory Test Results (Qualitative Urinalysis) by 
Final Dose (Subjects in The Safety Analysis Set for whom Maintenance 
Doses of The IMP were Determined) 
CT-10.3.1.1 Shift Tables of Clinical Laboratory Test Results (Serum Chemistry, 
Hematology, Urinalysis) (Safety Analysis Set) 
CT-10.3.1.2 Shift Tables of Clinical Laboratory Test Results (Serum Sodium) (Safety 
Analysis Set) 
CT-10.3.1.3 Shift Tables of Clinical Laboratory Test Results (Liver Function) (Safety 
Analysis Set) 
CT-10.3.2.1 Shift Tables of Clinical Laboratory Test Results (Serum Chemistry, 
Hematology, Urinalysis) by Underlying Disease Leading to SIADH (Safety 
Analysis Set) 
CT-10.3.2.2 Shift Tables of Clinical Laboratory Test Results (Serum Sodium) by 
Underlying Disease Leading to SIADH at Central Laboratory (Safety 
Analysis Set) 
CT-10.3.2.3 Shift Tables of Clinical Laboratory Test Results (Liver Function) by 
Underlying Disease Leading to SIADH (Safety Analysis Set) 


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CT-10.3.3.1 Shift Tables of Clinical Laboratory Test Results (Serum Chemistry, 
Hematology, Urinalysis) by Baseline Sodium Level (Safety Analysis Set) 
CT-10.3.3.2 Shift Tables of Clinical Laboratory Test Results (Serum Sodium) by 
Baseline Sodium Level (Safety Analysis Set) 
CT-10.3.3.3 Shift Tables of Clinical Laboratory Test Results (Liver Function) by 
Baseline Sodium Level (Safety Analysis Set) 
CT-10.3.4.1 Shift Tables of Clinical Laboratory Test Results (Serum Chemistry, 
Hematology, Urinalysis) by Maintenance Dose (Subjects in The Safety 
Analysis Set for whom Maintenance Doses of The IMP were Determined) 
CT-10.3.4.2 Shift Tables of Clinical Laboratory Test Results (Serum Sodium) by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-10.3.4.3 Shift Tables of Clinical Laboratory Test Results (Liver Function) by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-10.3.5.1 Shift Tables of Clinical Laboratory Test Results (Serum Chemistry, 
Hematology, Urinalysis) by Final Dose (Subjects in The Safety Analysis Set 
for whom Maintenance Doses of The IMP were Determined) 
CT-10.3.5.2 Shift Tables of Clinical Laboratory Test Results (Serum Sodium) by Final 
Dose (Subjects in The Safety Analysis Set for whom Maintenance Doses of 
The IMP were Determined) 
CT-10.3.5.3 Shift Tables of Clinical Laboratory Test Results (Liver Function) by Final 
Dose (Subjects in The Safety Analysis Set for whom Maintenance Doses of 
The IMP were Determined) 
CT-10.4 
Listing of Abnormal Laboratory Findings (Safety Analysis Set) 
CT-11.1 
Mean Change from Baseline in Vital Signs (Safety Analysis Set) 
CT-11.2 
Mean Change from Baseline in Vital Signs by Underlying Disease Leading 
to SIADH (Safety Analysis Set) 
CT-11.3 
Mean Change from Baseline in Vital Signs by Baseline Sodium Level 
(Safety Analysis Set) 


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CT-11.4     Mean Change from Baseline in Vital Signs by Maintenance Dose (Subjects in 
The Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-11.5 
Mean Change from Baseline in Vital Signs by Final Dose (Subjects in The 
Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-12.1.1 
Mean Change from Baseline in ECG Evaluations (Safety Analysis Set) 
CT-12.1.2 
Mean Change from Baseline in ECG Evaluations by Underlying Disease 
Leading to SIADH (Safety Analysis Set) 
CT-12.1.3 
Mean Change from Baseline in ECG Evaluations by Baseline Sodium Level 
(Safety Analysis Set) 
CT-12.1.4 
Mean Change from Baseline in ECG Evaluations by Maintenance Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 
CT-12.1.5 
Mean Change from Baseline in ECG Evaluations by Final Dose (Subjects in 
The Safety Analysis Set for whom Maintenance Doses of The IMP were 
Determined) 
CT-12.2.1 
Shift Table of 12-Lead ECG Findings (Normal/Abnormal Assessments) 
(Safety Analysis Set) 
CT-12.2.2 
Shift Table of 12-Lead ECG Findings (Normal/Abnormal Assessments) by 
Underlying Disease Leading to SIADH (Safety Analysis Set) 
CT-12.2.3 
Shift Table of 12-Lead ECG Findings (Normal/Abnormal Assessments) by 
Baseline Sodium Level (Safety Analysis Set) 
CT-12.2.4 
Shift Table of 12-Lead ECG Findings (Normal/Abnormal Assessments) by 
Maintenance Dose (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-12.2.5 
Shift Table of 12-Lead ECG Findings (Normal/Abnormal Assessments) by 
Final Dose (Subjects in The Safety Analysis Set for whom Maintenance 
Doses of The IMP were Determined) 
CT-12.3.1 
Incidence of Categorical Changes in ECG Evaluations (Safety Analysis Set) 
CT-12.3.2 
Incidence of Categorical Changes in ECG Evaluations by Underlying 
Disease Leading to SIADH (Safety Analysis Set) 


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CT-12.3.3 
Incidence of Categorical Changes in ECG Evaluations by Baseline Sodium 
Level (Safety Analysis Set) 
CT-12.3.4 
Incidence of Categorical Changes in ECG Evaluations by Maintenance 
Dose (Subjects in The Safety Analysis Set for whom Maintenance Doses of 
The IMP were Determined) 
CT-12.3.5 
Incidence of Categorical Changes in ECG Evaluations by Final Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 
CT-12.3.6 
Incidence of Categorical Changes in ECG Evaluations (Each Visit) (Safety 
Analysis Set) 
CT-12.3.7 
Incidence of Categorical Changes in ECG Evaluations by Underlying 
Disease Leading to SIADH (Each Visit) (Safety Analysis Set) 
CT-12.3.8 
Incidence of Categorical Changes in ECG Evaluations by Baseline Sodium 
Level (Each Visit) (Safety Analysis Set) 
CT-12.3.9 
Incidence of Categorical Changes in ECG Evaluations by Maintenance 
Dose (Each Visit) (Subjects in The Safety Analysis Set for whom 
Maintenance Doses of The IMP were Determined) 
CT-12.3.10 Incidence of Categorical Changes in ECG Evaluations by Final Dose (Each 
Visit) (Subjects in The Safety Analysis Set for whom Maintenance Doses of 
The IMP were Determined) 
CT-13.1 
Percentage of subjects with Abnormal Liver Function Test (Safety Analysis 
Set) 
CT-13.2 
Percentage of subjects with Abnormal Liver Function Test by Underlying 
Disease Leading to SIADH (Safety Analysis Set) 
CT-13.3 
Percentage of subjects with Abnormal Liver Function Test by Baseline 
Sodium Level (Safety Analysis Set) 
CT-13.4 Percentage of subjects with Abnormal Liver Function Test by Maintenance Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 
CT-13.5 
Percentage of subjects with Abnormal Liver Function Test by Final Dose 
(Subjects in The Safety Analysis Set for whom Maintenance Doses of The 
IMP were Determined) 


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PDT-1 
Descriptive Statistics for Daily Urine Volume (mL) (Pharmacodynamics 
Analysis Set) 
PDT-2 
Descriptive Statistics for Daily Fluid Intake (mL) (Pharmacodynamics 
Analysis Set) 
PDT-3 
Descriptive Statistics for Daily Fluid Balance (mL) (Pharmacodynamics 
Analysis Set) 
PDT-4 
Descriptive Statistics for Serum Osmolality (mOsm/kg) 
(Pharmacodynamics Analysis Set) 
PDT-5 
Descriptive Statistics for Urine Osmolality (mOsm/kg) (Pharmacodynamics 
Analysis Set) 
PDT-6 
Descriptive Statistics for Daily Urine Excretion of Sodium (mEq) 
(Pharmacodynamics Analysis Set) 
PDT-7 
Descriptive Statistics for Plasma AVP Concentration (ng/L) 
(Pharmacodynamics Analysis Set) 
CF-1.1 
Transition Diagram for Serum Sodium Concentration for Efficacy Analysis 
Set 
CF-1.2.1 
Transition Diagram for Serum Sodium Concentration for Maintenance 
Dose- setting Set 
CF-1.2.2 
Transition Diagram for Serum Sodium Concentration After Maintenance 
Dose Determination for Maintenance Dose-setting Set 
CF-1.3 
Transition Diagram for Serum Sodium Concentration by Underlying 
Disease Leading to SIADH for Efficacy Analysis Set 
CF-1.4.1 
Transition Diagram for Serum Sodium Concentration by Underlying 
Disease Leading to SIADH for Maintenance Dose-setting Set 
CF-1.4.2 
Transition Diagram for Serum Sodium Concentration After Maintenance 
Dose Determination by Underlying Disease Leading to SIADH for 
Maintenance Dose-setting Set 
CF-1.5 
Transition Diagram for Serum Sodium Concentration by baseline sodium 
level for Efficacy Analysis Set 
CF-1.6.1 
Transition Diagram for Serum Sodium Concentration by baseline sodium 
level for Maintenance Dose-setting Set 


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CF-1.6.2 
Transition Diagram for Serum Sodium Concentration After Maintenance 
Dose Determination by baseline sodium level for Maintenance Dose-setting 
Set 
CF-1.7.1 
Transition Diagram for Serum Sodium Concentration by Maintenance Dose 
for Maintenance Dose-setting Set 
CF-1.7.2 Transition Diagram for Serum Sodium Concentration After Maintenance 
Dose Determination by Maintenance Dose for Maintenance Dose-setting 
Set 
CF-1.7.3 
Transition Diagram for Serum Sodium Concentration by Final Dose for 
Maintenance Dose-setting Set 
CF-1.8 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration for Efficacy Analysis Set 
CF-1.9.1 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration for Maintenance Dose-setting Set 
CF-1.9.2 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration After Maintenance Dose Determination for Maintenance 
Dose-setting Set 
CF-1.10 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration by Underlying Disease Leading to SIADH for Efficacy 
Analysis Set 
CF-1.11.1 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration by Underlying Disease Leading to SIADH for Maintenance 
Dose-setting Set 
CF-1.11.2 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration After Maintenance Dose Determination by Underlying 
Disease Leading to SIADH for Maintenance Dose-setting Set 
CF-1.12 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration by baseline sodium level for Efficacy Analysis Set 
CF-1.13.1 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration by baseline sodium level for Maintenance Dose-setting Set 
CF-1.13.2 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration After Maintenance Dose Determination by baseline sodium 
level for Maintenance Dose-setting Set 


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CF-1.14.1 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration by Maintenance Dose for Maintenance Dose-setting Set 
CF-1.14.2 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration After Maintenance Dose Determination by Maintenance 
Dose for Maintenance Dose-setting Set 
CF-1.14.3 
Transition Diagram for Change from Baseline in Serum Sodium 
Concentration by Final Dose for Maintenance Dose-setting Set 


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Appendix 2 
List of Subject Data Listings 
DREAS-1 
Discontinued Subjects and Reason for Discontinuation (IMP Administered 
Subjects) 
SUBEX-1 
Subjects Excluded From Analysis Set (IMP Administered Subjects) 
DEMOG-1 
Demographic and Baseline Characteristics (IMP Administered Subjects) 
SMED-1 
Investigational Medicinal Product Compliance (IMP Administered 
Subjects) 
PDEV-1 
Protocol Deviations (IMP Administered Subjects) 
AE-1 
Adverse Events (IMP Administered Subjects) 
AE-2 
Adverse Events Observed Before Start of Investigational Medicinal 
Product Administration (IMP Administered Subjects) 
LAB-1 
Laboratory Test Results - Serum Chemistry (IMP Administered Subjects) 
LAB-2 
Laboratory Test Results - Hematology (IMP Administered Subjects) 
LAB-3 
Laboratory Test Results - Urinalysis (IMP Administered Subjects) 
PDATA-1 
Study Completion Status and Reason for Discontinuation (IMP 
Administered Subjects) 
PDATA-2 
Inclusion Criteria and Exclusion Criteria Not Met (Screened Subjects) 
PDATA-3 
Medical History and Complications (IMP Administered Subjects) 
PDATA-4.1 Concomitant Medications (IMP Administered Subjects) 
PDATA-4.2 Concomitant Therapy (IMP Administered Subjects) 
PDATA-4.3 Treatment for Hyponatremia in SIADH Prior to Trial (IMP Administered 
Subjects) 
PDATA-4.4 Concomitant Medications (Antineoplastic Agents) (IMP Administered 
Subjects) 
PDATA-4.5 Concomitant Medications (Saline) (IMP Administered Subjects) 
PDATA-4.6 Concomitant Medications (Infusion Solution other than Saline) (IMP 
Administered Subjects) 
PDATA-4.7 Concomitant Medications (Sodium Chloride) (IMP Administered 
Subjects) 


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PDATA-4.8 Concomitant Medications (Affects Sodium Concentration) (IMP 
Administered Subjects) 
PDATA-5 
Vital Signs (IMP Administered Subjects) 
PDATA-6 
Electrocardiogram Results (IMP Administered Subjects) 
PDATA-7 
Pharmacokinetic Blood Draw Time and Plasma Drug Concentration (IMP 
Administered Subjects) 
PDATA-8 
Screen Failures 
PDATA-9 
Serum Osmolality and Plasma AVP Concentration at Central Laboratory 
(IMP Administered Subjects) 
PDATA-10 
Serum Osmolality and Plasma AVP Concentration at Each Center (IMP 
Administered Subjects) 
PDATA-11 
Daily Urine Volume, Daily Fluid Intake, Daily Fluid Balance, Urine 
Sodium Concentration, Daily Urine Excretion of Sodium and Urine 
Osmolality (IMP Administered Subjects) 
PDATA-12 
Past medical history of bilateral oophorectomy or hysterectomy (IMP 
Administered Subjects) 
PDATA-13 
Information on Hospitalization (IMP Administered Subjects) 
PDATA-14 
Subject lost to Follow-up (IMP Administered Subjects) 
PDATA-15 
Fluid Intake Restriction Compliance (IMP Administered Subjects) 
EFF-1.1 
Serum Sodium Concentration Measured at Central Laboratory (IMP 
Administered Subjects) 
EFF-1.2 
Serum Sodium Concentration Measured at Each Center (IMP 
Administered Subjects) 
EFF-1.3 
Serum Sodium Concentration Measured at Each Center Diagnosis and 
Treatment of SIADH Prior to Trial (IMP Administered Subjects) 
EFF-2.1 
Clinical Symptom Associated with Hyponatremia (IMP Administered 
Subjects) 
EFF-2.2 
Clinical Symptom Associated with Hyponatremia Diagnosis and 
Treatment of SIADH Prior to Trial (IMP Administered Subjects)