A Study of OPC-41061 Orally Disintegrating (OD) Tablets Using 2 Different Formulations and 2 Dosing Regimens in Healthy Adult Male Subjects
Phase: PHASE1
Conditions: Healthy Adult Male
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Single-center, Open-label, Randomized, 3-Period, 3-Way, Crossover Bioequivalence 
Study of OPC-41061 Orally Disintegrating Tablets Using 2 Different Formulations 
and 2 Different Dosing Regimens in Healthy Adult Male Subjects 
 
 
 
 
NCT Number: NCT02994394 
PRT NO.: 156-102-00136 
Version Date: 25 November 2016 (Version 1.0) 

Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
 
Tolvaptan (OPC-41061) 
 
CLINICAL PROTOCOL 
 
A Single-center, Open-label, Randomized, 3-Period, 3-Way, Crossover Bioequivalence 
Study of OPC-41061 Orally Disintegrating Tablets Using 2 Different Formulations and 2 
Different Dosing Regimens in Healthy Adult Male Subjects 
 
Protocol No. 156-102-00136 
 
 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase:  
 
1 
 
Sponsor: 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
 
 
 
 
2-9 Kandatsukasa-machi, Chiyoda-ku,  
 
 
 
 
 
 
Tokyo, 101-8535, Japan 
 
Immediately Reportable Event  
Single Case Processing team, 
Pharmacovigilance Department, Otsuka 
Pharmaceutical Co., Ltd. 
3-2-27 Otedori, Chuo-ku, Osaka-shi, Osaka, 
540-0021, Japan 
 
 
 
 
 
 
e-mail:  IRE_156-102-00136@otsuka.jp 
 
 
Issue Date: 
 
 
 
 
25 Nov 2016 
 
Version No.:  
 
 
 
1.0 
 
 
 
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical Co., Ltd. 
Name of Investigational Medicinal Product:  Tolvaptan 
(OPC-41061) 
Protocol No.: 156-102-00136 
 
Trial Title: 
A Single-center, Open-label, Randomized, 3-Period, 3-Way, 
Crossover Bioequivalence Study of OPC-41061 Orally 
Disintegrating (OD) Tablets Using 2 Different Formulations 
and 2 Dosing Regimens in Healthy Adult Male Subjects 
Trial Objectives: 
To assess the bioequivalence of OPC-41061 OD tablets and 
OPC-41061 conventional tablets at 15 and 30 mg in healthy 
adult male subjects 
Phase of 
Development: 
Phase:  1  
Type of trial:  Bioequivalence study 
Trial Design: 
A single-center, open-label, randomized, 3-period, 3-way, 
crossover study using 2 formulations in 2 dosing regimens, 
will be conducted in 2 cohorts. 
 
[Cohort 1] 
Dose 
Group 
Period 1 
Period 2 
Period 3 
15 mg 
Conventional 
tablet first 
Conventional 
tablet 
OD tablet 
without 
water 
OD tablet 
with water 
OD tablet 
with water 
first 
OD tablet 
with water 
Conventional 
tablet 
OD tablet 
without 
water 
OD tablet 
without 
water first 
OD tablet 
without 
water 
OD tablet 
with water 
Conventional 
tablet 
 
[Cohort 2] 
Dose 
Group 
Period 1 
Period 2 
Period 3 
30 mg 
Conventional 
tablet first 
Conventional 
tablet 
OD tablet 
without 
water 
OD tablet 
with water 
OD tablet 
with water 
first 
OD tablet 
with water 
Conventional 
tablet 
OD tablet 
without 
water 
OD tablet 
without 
water first 
OD tablet 
without 
water 
OD tablet 
with water 
Conventional 
tablet 
A washout period of 72 hours will be set from postdose in 
Period 1 until predose in Period 2 and from postdose in Period 
2 until predose in Period 3.  This study consists of a main 
study and an add-on subject study in additional subjects. 
Subject Population: 
A total of 84 healthy adult male subjects at least 20 years and 
less than 40 years of age will be enrolled.  
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Inclusion/Exclusion 
Criteria:  
Inclusion Criteria: 
1) Japanese males at least 20 years and less than 40 years 
of age at the time of informed consent 
2) Body weight of at least 50.0 kg  
3) BMI [body weight in kg / (height in m)2] of at least 
17.6 kg/m2 and less than 25.0 kg/m2 
4) Judged by the investigator or subinvestigator to be 
capable of providing written informed consent prior to 
the start of any trial-related procedures and capable of 
complying with the trial procedures for this study. 
 
Main Exclusion Criteria: 
1) Judged by the investigator, subinvestigator, or sponsor 
to have a clinically significant abnormality in results of 
the screening examination (including a notable 
deviation from the site’s standard values) or a medical 
history that could place the subject at risk or affect the 
evaluation of drug absorption, distribution, metabolism, 
or excretion 
2) History of alcohol or drug dependence or abuse within 
2 years prior to the trial 
3) History or current symptoms of hepatitis or acquired 
immunodeficiency syndrome (AIDS) or positive test 
results for hepatitis B surface antigen (HBsAg), anti-
hepatitis C virus (HCV), or human immunodeficiency 
virus (HIV), or judged to have syphilis based on the 
results of Treponema pallidum (TP) antibody test or 
rapid plasma reagin (RPR) test 
4) History of any severe drug allergy 
5) Positive results in alcohol screening test or urine drug 
screening test at time of screening examination or trial 
site admission 
6) Use of any other investigational medicinal product 
(IMP) within 120 days prior to Period 1 IMP 
administration 
7) Consumption of any food or beverage containing St. 
John’s wort within 14 days prior to Period 1 IMP 
administration 
8) Consumption of any food or beverage containing 
grapefruit, Seville orange, or star fruit within 7 days 
prior to Period 1 IMP administration  
9) Judgment by the investigator or subinvestigator that the 
subject should not participate in the study for any other 
reason 
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Trial Site:  
Soseikai Medical Group Fukuoka Mirai Hospital 
Investigational 
Medicinal Product, 
Dose and Regimen, 
Treatment Period, 
Formulation, and 
Route of 
Administration: 
[Test drug: Tolvaptan OD tablet] 
Cohort 
Dose 
(mg) 
Active 
Ingredient 
(Content 
per tablet) 
Dose per 
Administration 
Dosing Regimen 
(Single oral 
administration in 
a fasting state) 
1 
15 
Tolvaptan 
15 mg 
1 tablet 
With water: 
Administered with 
approx. 150 mL of 
water. 
2 
30 
Tolvaptan 
30 mg 
Without water: 
Tablet 
disintegrated on 
the tongue and 
swallowed 
immediately with 
saliva 
 
[Comparator: Tolvaptan conventional tablet] 
Cohort 
Dose 
(mg) 
Active 
Ingredient 
(Content 
per tablet) 
Dose per 
Administration 
Dosing Regimen 
(Single oral 
administration in 
a fasting state) 
1 
15 
Tolvaptan 
15 mg 
1 tablet 
Administered with 
approx. 150 mL of 
water. 
2 
30 
Tolvaptan 
30 mg 
 
Duration of treatment:  Single administration a total of 3 times 
on 3 separate days 
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Variables: 
[Bioequivalence] 
1) Primary variables:  AUCt and Cmax of tolvaptan 
2) Reference variables: 
 Plasma concentration-time profile of tolvaptan 
 AUC∞, MRT∞, tmax, λz, AUC_%Extrap, t1/2,z, 
CL/F, CL/F/BW, and tlast of tolvaptan 
 By-subject ratios of AUCt, Cmax, AUC∞, MRT∞, 
and λz of tolvaptan for administration of OD tablet 
with and without water to those for administration 
of conventional tablet 
 Difference (value for OD tablet minus value for 
conventional tablet) in tmax by subject between 
administration of OD tablet without water and 
administration of conventional tablet and between 
administration of OD tablet with water and 
administration of conventional tablet  
[Safety Variables] 
Body weight, vital signs (body temperature, blood pressure, 
and pulse rate), clinical laboratory tests, 12-lead 
electrocardiography (ECG), physical examination, and adverse 
events 
Statistical Methods: 
For the AUCt and Cmax of tolvaptan, data will be log-
transformed and analysis of variance (ANOVA) will be 
performed using group (group receiving conventional tablet 
first, group receiving OD tablet without water first, and group 
receiving tolvaptan OD tablet with water first), formulation, 
dosing regimen, subjects within group, and administration 
period (Period 1, Period 2, and Period 3) as factors. 
For the AUCt and Cmax of tolvaptan, the 90% confidence 
interval (CI) of the ratio of the geometric mean values for the 2 
formulations (OD tablet without water vs conventional tablet 
and value for OD tablet with water vs conventional tablet) will 
be calculated. 
If evaluable data cannot be obtained for a subject for all 
periods (1, 2, and 3), sensitivity analysis will be performed 
including such subjects. 
Scheduled Duration 
of the Trial: 
Duration of the trial:  Dec 2016 to Dec 2017 
Scheduled duration of individual subjects’ participation:  
Maximum of 37 days (3 to 29 days for screening period and 8 
days for treatment period)  
 
 
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Table of Contents  
Protocol Synopsis ........................................................................................... 2 
Table of Contents ........................................................................................... 6 
List of In-text Tables ................................................................................... 11 
List of In-text Figures .................................................................................. 12 
List of Abbreviations and Definitions of Terms ....................................... 13 
1 
Introduction ........................................................................................ 14 
1.1 
Nonclinical Data ................................................................................................15 
1.2 
Clinical Data ......................................................................................................17 
1.2.1 
Single Oral Dose Study (156-00-001) ............................................................17 
1.3 
Known and Potential Risks and Benefits ..........................................................18 
2 
Trial Rationale and Objectives.......................................................... 19 
2.1 
Trial Rationale ...................................................................................................19 
2.2 
Dosing Rationale ...............................................................................................20 
2.2.1 
Regimens ........................................................................................................20 
2.2.2 
Dose Levels ....................................................................................................20 
2.3 
Trial Objectives .................................................................................................20 
3 
Trial Design ......................................................................................... 21 
3.1 
Type/Design of Trial .........................................................................................21 
3.2 
Trial Treatments ................................................................................................22 
3.2.1 
Investigational Medicinal Products ................................................................22 
3.2.1.1 
Tolvaptan OD Tablet...................................................................................22 
3.2.1.2 
Tolvaptan Conventional Tablet ...................................................................22 
3.2.2 
Treatment Period ............................................................................................23 
3.3 
Trial Population .................................................................................................23 
3.3.1 
Number of Subjects and Description of Population .......................................23 
3.3.2 
Subject Selection and Numbering ..................................................................24 
3.4 
Eligibility Criteria..............................................................................................24 
3.4.1 
Informed Consent ...........................................................................................24 
3.4.2 
Inclusion Criteria ............................................................................................24 
3.4.3 
Exclusion Criteria ...........................................................................................25 
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3.5 
Variables ............................................................................................................26 
3.5.1 
Bioequivalence ...............................................................................................26 
3.5.1.1 
Primary Variable .........................................................................................26 
3.5.1.2 
Reference Variables ....................................................................................26 
3.5.2 
Safety ..............................................................................................................27 
3.6 
Measures to Minimize/Avoid Bias ....................................................................27 
3.7 
Trial Procedures ................................................................................................27 
3.7.1 
Schedule of Assessments (Both Cohorts) .......................................................29 
3.7.1.1 
Screening .....................................................................................................29 
3.7.1.2 
Day Before IMP Administration in Period 1 (Day −1) ...............................29 
3.7.1.3 
Day Before IMP Administration in Periods 2 and 3 (Day 3 and 6) ............30 
3.7.1.4 
Day of IMP Administration (Day 1, 4, and 7) ............................................30 
3.7.1.4.1 
Before IMP Administration .....................................................................30 
3.7.1.4.2 
Subject Enrollment and Treatment Assignment (Only on Day 1) ..........30 
3.7.1.4.3 
Subject Replacement (Only on Day 1) ....................................................30 
3.7.1.4.4 
IMP Administration .................................................................................30 
3.7.1.4.5 
After IMP Administration .......................................................................31 
3.7.1.5 
Day After IMP Administration (Day 2, 5, and 8) .......................................31 
3.7.1.6 
At Discontinuation ......................................................................................31 
3.7.1.7 
Follow-up Examination ...............................................................................32 
3.7.2 
Safety Assessments .........................................................................................32 
3.7.2.1 
Adverse Events............................................................................................32 
3.7.2.2 
Clinical Laboratory Assessments ................................................................32 
3.7.2.3 
Physical Examination and Vital Signs (Body Temperature, Blood 
Pressure, Pulse Rate) ...................................................................................33 
3.7.2.3.1 
Physical Examination ..............................................................................33 
3.7.2.3.2 
Vital Signs (Body Temperature, Blood Pressure, Pulse Rate) ................33 
3.7.2.4 
Electrocardiogram Assessments..................................................................34 
3.7.2.5 
Body Weight ...............................................................................................34 
3.7.3 
Pharmacokinetic Assessments ........................................................................34 
3.7.3.1 
Time Points .................................................................................................34 
3.7.3.2 
Blood Collection Procedure and Sample Treatment ...................................35 
3.7.3.3 
Transportation .............................................................................................35 
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3.7.3.4 
Plasma Drug Concentration Measurement..................................................35 
3.7.3.5 
Reporting of Measurement Results .............................................................35 
3.7.3.6 
Handling of Remaining Samples ................................................................35 
3.7.4 
End of Trial .....................................................................................................35 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures ......................................36 
3.8.1 
Entire Trial ......................................................................................................36 
3.8.2 
Individual Site .................................................................................................36 
3.8.3 
Individual Subject Discontinuation ................................................................36 
3.8.3.1 
Treatment Discontinuation ..........................................................................36 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation ...............................36 
3.8.3.3 
Withdrawal of Consent ...............................................................................37 
3.9 
Screen Failures ..................................................................................................37 
3.10 
Definition of Completed Subjects .....................................................................37 
3.11 
Definition of Subjects Lost to Follow-up ..........................................................38 
3.12 
Subject Compliance ...........................................................................................38 
3.13 
Protocol Deviations ...........................................................................................38 
4 
Restrictions .......................................................................................... 38 
4.1 
Prohibited Medications......................................................................................38 
4.2 
Other Restrictions ..............................................................................................39 
4.2.1 
Subject Admission ..........................................................................................39 
4.2.2 
Self Care .........................................................................................................39 
4.2.3 
Restricted Foods .............................................................................................39 
4.2.4 
Prohibition of the Supine Position ..................................................................40 
5 
Reporting of Adverse Events ............................................................. 40 
5.1 
Definitions .........................................................................................................40 
5.2 
Eliciting and Reporting Adverse Events ...........................................................42 
5.3 
Immediately Reportable Events ........................................................................42 
5.4 
Potential Drug-Induced Liver Injury .................................................................42 
5.5 
Pregnancy ..........................................................................................................43 
5.6 
Procedure for Breaking the Blind ......................................................................43 
5.7 
Follow-up of Adverse Events ............................................................................43 
5.7.1 
Follow-up of Nonserious Adverse Events ......................................................43 
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5.7.2 
Follow-up of Serious Adverse Events ............................................................44 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring After 
Last Scheduled Contact ..................................................................................44 
6 
Pharmacokinetic/pharmacodynamic Analysis ................................ 45 
6.1 
Pharmacokinetic Analysis .................................................................................45 
6.1.1 
Primary Variables ...........................................................................................45 
6.1.2 
Reference Variables ........................................................................................45 
6.1.3 
Datasets for Analysis ......................................................................................45 
6.1.4 
Calculations of PK Parameters .......................................................................45 
6.1.5 
Calculation of Descriptive Statistics ...............................................................46 
6.2 
Pharmacodynamic Analysis ..............................................................................46 
7 
Statistical Analysis .............................................................................. 46 
7.1 
Sample Size .......................................................................................................46 
7.2 
Datasets for Analysis .........................................................................................46 
7.2.1 
Safety Analysis Set .........................................................................................46 
7.2.2 
Bioequivalence Analysis Set ..........................................................................47 
7.3 
Handling of Missing Data .................................................................................47 
7.4 
Primary and Reference Endpoint Variables ......................................................47 
7.4.1 
Primary Variable Analysis ..............................................................................47 
7.4.2 
Reference Variable Analyses ..........................................................................47 
7.5 
Analysis of Demographic and Baseline Characteristics....................................48 
7.6 
Safety Analysis ..................................................................................................48 
7.6.1 
Adverse Events ...............................................................................................48 
7.6.2 
Clinical Laboratory Data ................................................................................48 
7.6.3 
Physical Examination and Vital Signs ............................................................48 
7.6.4 
Electrocardiogram Data ..................................................................................49 
7.7 
Decision on Whether to Conduct an Add-on Subject Study .............................49 
8 
Management of Investigational Medicinal Product and 
Reference Product .............................................................................. 49 
8.1 
Packaging and Labeling ....................................................................................49 
8.2 
Storage ...............................................................................................................50 
8.3 
Accountability ...................................................................................................50 
8.4 
Returns and Destruction ....................................................................................50 
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8.5 
Reporting of Product Quality Complaints .........................................................50 
8.5.1 
Eliciting and Reporting Product Quality Complaints .....................................51 
8.5.2 
Information Required for Reporting Purposes ...............................................51 
8.5.3 
Return Process ................................................................................................51 
8.5.4 
Assessment/Evaluation ...................................................................................51 
9 
Records Management ......................................................................... 52 
9.1 
Source Documents .............................................................................................52 
9.2 
Data Collection ..................................................................................................52 
9.3 
File Management at the Trial Site .....................................................................53 
9.4 
Records Retention at the Trial Site....................................................................53 
10 
Quality Control and Quality Assurance ........................................... 53 
10.1 
Monitoring .........................................................................................................53 
10.2 
Auditing .............................................................................................................54 
11 
Ethics and Responsibility ................................................................... 54 
12 
Confidentiality .................................................................................... 54 
13 
Amendment Policy .............................................................................. 55 
14 
Publication Authorship Requirements ............................................. 55 
15 
References ............................................................................................ 57 
 
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List of In-text Tables 
Table 3.4.2-1 
Inclusion Criteria .......................................................................... 25 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 25 
Table 3.7-1 
Schedule of Assessments .............................................................. 28 
Table 3.7.2.2-1 
Clinical Laboratory Assessments .................................................. 33 
 
 
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List of In-text Figures 
Figure 1.1-1 
Dissolution Profile of Tolvaptan Conventional Tablet 15 mg 
and Tolvaptan OD Tablet 15 mg. ................................................. 15 
Figure 1.1-2 
Dissolution Profile of Tolvaptan Conventional Tablet 30 mg 
and Tolvaptan OD Tablet 30 mg. ................................................. 16 
Figure 3.1-1 
Trial Design Schematic ................................................................. 22 
Figure 3.7-1 
Trial Procedures ............................................................................ 27 
 
 
 
 
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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC∞ 
Area under the concentration-time curve from time zero to infinity 
AUCt 
Area under the concentration-time curve from time zero to the last observable 
concentration at time t 
AUC_%Extrap 
Percentage of AUC due to extrapolation from tlast to infinity 
[(AUC∞ - AUCt) / AUC∞ × 100] 
BMI 
Body mass index 
BUN 
Blood urea nitrogen  
CIOMS 
Council for International Organizations of Medical Science 
CL/F 
Apparent clearance of drug from plasma after extravascular administration 
CL/F/BW 
CL/F normalized in body weight 
Cmax 
Maximum (peak) plasma concentration 
CPK 
Creatine phosphokinase 
DILI 
Drug Induced Liver Injury 
EDC 
Electronic data capture 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
LDH 
Lactic dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT∞ 
Mean residence time from time zero to infinity 
OD 
Orally disintegrating 
PQC 
Product quality complaint 
QTcB 
QT interval corrected for heart rate by Bazett’s formula 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
t1/2,z 
Terminal-phase elimination half-life 
TEAE 
Treatment-emergent adverse event 
tlast 
Time of last measurable [positive] concentration 
tmax 
Time to maximum [peak] plasma concentration 
λz 
Apparent terminal-phase disposition rate constant (first-order) 
 
 
 
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1 
Introduction 
Tolvaptan is a nonpeptide, cyclic adenosine monophosphate (cAMP)-dependent, arginine 
vasopressin (AVP) V2 receptor antagonist synthesized by Otsuka Pharmaceutical Co., 
Ltd.  Tolvaptan increases water excretion (water diuresis) without affecting electrolyte 
excretion by inhibiting water reabsorption at the renal collecting ducts.  The compound 
was granted marketing approval in Japan on 27 Oct 2010 under the trade name of 
“Samsca® tablets 15 mg” for the treatment of “volume overload in heart failure when an 
adequate response is not obtained with other diuretics (eg, loop diuretics).”  Subsequently, 
tolvaptan was granted additional indications for the “treatment of body fluid retention in 
hepatic cirrhosis when an adequate response is not obtained with other diuretics (eg, loop 
diuretics)” on 13 Sep 2013 and “Suppression of progression of autosomal dominant 
polycystic kidney disease (ADPKD) in patients with increased kidney volume and a rapid 
rate of increase” on 24 Mar 2014 and is currently in the reexamination period.  Samsca 
tablets 7.5 mg and tablets 30 mg were respectively approved on 04 Feb 2013 and 24 Mar 
2014. 
In the United States, the drug acquired marketing authorization for “hypervolemic and 
euvolemic hyponatremia in patients with heart failure and syndrome of inappropriate 
antidiuretic hormone (SIADH) on 19 May 2009.  In Europe, it was approved for the 
“treatment of adult patients with hyponatremia secondary to SIADH” on 03 Aug 2009.  
Tolvaptan has now been approved in over 40 countries though for different indications. 
Samsca tablets are used in the clinical setting in patients covering a wide age range and 
with different disorders, including those with relatively severe heart failure in whom an 
adequate response is not obtained with other diuretics.  Only the tablet formulations of 
tolvaptan are available, but other dosage forms that are easier for the patients to use 
should be added to the lineup for better medication adherence. In particular, swallowing 
tablets can be problematic in elderly patients with swallowing difficulties.  Clinicians 
desire an orally-disintegrating (OD) tablet formulation so that such patients can use the 
drug without water.  This study has been planned in order to develop an OD tablet 
formulation to add to the currently available non-OD tablet for increased treatment 
options and also for better adherence. 
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1.1 
Nonclinical Data 
Tolvaptan OD tablet 15 mg showed a similar dissolution profile to the tolvaptan 
conventional tablet 15 mg in solution with a pH of 6.8, the pH level typically found in the 
small intestine where the drug is absorbed (2nd fluid for dissolution test of the Japanese 
Pharmacopoeia).  
 
Figure 1.1-1 
Dissolution Profile of Tolvaptan Conventional Tablet 15 mg 
and Tolvaptan OD Tablet 15 mg.  Volume of Dissolution 
Medium, 900 mL; Test Method, Paddle Method at 50 rpm 
(Number of Vessels, 3; Mean ± Standard Deviation) 
pH 1.2:  JP 1st Fluid for Dissolution Test, 
pH 4.0:  Diluted McIlvaine’s Buffer, 
pH 6.8:  JP 2nd Fluid for Dissolution Test 
 
Time (min) 
Time (min) 
Time (min) 
Time (min) 
Water
Dissolution rate (%) 
Conventional 
tablet 15 mg 
OD tablet 15 mg 
Dissolution rate (%) 
Dissolution rate (%) 
Dissolution rate (%) 
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Tolvaptan OD tablet 30 mg showed a similar dissolution profile to the tolvaptan 
conventional tablet 30 mg in a solution with a pH of 6.8, the pH level typically found in 
the small intestine where the drug is absorbed (2nd fluid for dissolution test of the 
Japanese Pharmacopoeia). 
 
 
Figure 1.1-2 
Dissolution Profile of Tolvaptan Conventional Tablet 30 mg 
and Tolvaptan OD Tablet 30 mg.  Volume of Dissolution 
Medium, 900 mL; Test Method, Paddle Method at 50 rpm 
(Number of Vessels, 3; Mean ± Standard Deviation) 
pH 1.2:  JP 1st Fluid for Dissolution Test, 
pH 4.0:  Diluted McIlvaine’s Buffer, 
pH 6.8:  JP 2nd Fluid for Dissolution Test 
 
Time (min) 
Time (min) 
Time (min) 
Time (min) 
Dissolution rate (%) 
Water
Conventional 
tablet 30 mg 
OD tablet 30 mg 
Dissolution rate (%) 
Dissolution rate (%) 
Dissolution rate (%) 
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1.2 
Clinical Data 
No prior clinical study has been conducted using the same tolvaptan OD tablet as that to 
be used in this study.  The results of a single-dose study conducted in 2001 using the 
conventional tablets 15 mg and 30 mg (156-00-001) are discussed below. 
1.2.1 
Single Oral Dose Study (156-00-001) 
OPC-41061 15 to 120 mg was administered once orally to 40 healthy adult male 
volunteers under fasted conditions. 
1) Pharmacokinetic Results 
 Plasma pharmacokinetics of OPC-41061 after dosing of 15 to 120 mg showed 
large inter-individual variability.  DM-4103 showed the highest plasma 
concentration (Cmax and AUCt) and is therefore considered the primary metabolite 
of OPC-41061.  Among OPC-41061 metabolites, MOP-21826 was consistently 
below the lower limit of quantitation throughout the study period in all subjects 
(treated with 60 mg or 90 mg). 
 The AUCt and Cmax of OPC-41061 showed a fairly dose-dependent increase 
without obvious nonlinear changes as the dose increased (15 to 120 mg).  
Statistical evaluation confirmed dose proportionality (linearity) in AUCt but not in 
Cmax.  The t1/2,z of OPC-41061 was prolonged as the dose increased.  The mean 
t1/2,z in the 120 mg group was about 3 times that in the 15 mg group (9.33 hours 
vs 3.33 hours). 
 The cumulative urinary excretion of OPC-41061 had mostly reached plateau by 
48 hours postdose in all subjects.  The fe,48h of OPC-41061 was less than 1% in 
all subjects, indicating urine excretion does not account much for elimination of 
OPC-41061 from the system.  Among metabolites, urinary concentrations of DM-
4103, DM-4105, and MOP-21826 were consistently below the lower limit of 
quantitation in all subjects treated with 60 mg or 90 mg. 
2) Pharmacological Results 
 Twenty-four-hour cumulative urine volume dose-dependently increased, and, in 
the highest dose (120 mg) group, it reached 11945.8 mL, approximately 4.6 times 
that in the placebo group.  The urine excretion rate until 8 hours postdose (urine 
was pooled in 2-hour periods until 8 hours postdose) increased to approximately 
700 to 800 mL/h (in 60 to 120 mg groups).  It subsequently decreased, but 
diuretic effects were observed until 24 hours postdose in the 60 to 120 mg groups. 
 No marked increase or dose-dependent change was observed in 24-hour 
cumulative urine sodium excretion.  Twenty-four-hour cumulative urine 
potassium excretion increased with dose. 
 Urine osmolality decreased from immediately after dosing (from the interval of 0 
to 2 hours postdose) accompanied by hypotonic urine and a high positive value 
for free water clearance from immediately after dosing.  These water diuretic 
effects lasted longer at higher dose levels. 
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 Plasma AVP concentration increased after dosing and remained high at 24 hours 
postdose.  Serum sodium concentration increased after dosing but remained 
within normal physiological limits.  No notable change was observed in serum 
potassium concentration. 
 Fluid balance showed a negative value in the interval of 0 to 2 hours in a dose-
dependent manner but showed gains from Day 2. 
3) Safety Results 
 The incidence of adverse events in the study was 50.0% (21/42 subjects) in the 
OPC-41061 groups and 14.3% (2/14 subjects) in the placebo group.  The 
incidence of adverse events at least possibly related to the investigational 
medicinal products (= adverse drug reactions [ADRs]) was 45.2% (19/42 
subjects) and 7.1% (1/14 subjects), respectively. 
 By dose, the incidence of adverse events (in the descending order) was 100% (6/6 
subjects) in the 120 mg and 90 mg groups, 41.7% (5/12 subjects) in the 30 mg 
group, and 33.3% (2/6 subjects) in the 15 mg, 45 mg, and placebo groups.  No 
adverse event was reported in the 60 mg group. 
 Frequent adverse events (≥ 5% incidence) in the OPC-41061 groups were “thirst” 
(8 subjects), “nasopharyngitis” (4 subjects), and “blood osmolarity increased,” 
“blood uric acid increased,” and “headache NOS” (3 subjects each). 
 Serious adverse events (“sinus arrest” and “bradycardia NOS”) occurred in 1 
subject in the 30 mg group.  A causal relationship between these events and OPC-
41061 could not be ruled out, but both events resolved without intervention. 
 On laboratory values, no clinically significant variations were seen in any group 
including the placebo group. 
 On vital signs (blood pressure, pulse rate, and body temperature), no clinically 
significant changes were seen excluding the serious adverse events reported in the 
30 mg group.  Body weight decreased after dosing in all groups.  The decrease 
was larger in the OPC-41061 groups than in the placebo group.  The mean 
decrease in 24 hours after dosing was 1.42 to 2.20 kg in the OPC-41061 groups 
and 0.89 kg in the placebo group. 
 On electrocardiogram (ECG) findings, 1 subject in the 30 mg group experienced 
serious adverse events (“sinus arrest” and “bradycardia NOS”).  Two subjects in 
the 90 mg group also had tachycardia (mild).  These changes were judged to be 
“abnormal.”  However, they were transient changes and resolved without 
intervention. 
 
1.3 
Known and Potential Risks and Benefits 
In patients with body fluid retention in heart failure, ADRs including laboratory test 
abnormalities were reported in 143 out of 213 subjects (67.1%) included in the safety 
dataset of a clinical study conducted in Japan.  Common ADRs were thirst (65 events or 
30.5%), blood urea nitrogen increased (28 events or 13.1%), and blood uric acid 
increased (20 events or 9.4%) among others (at the time of approval). 
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In patients with body fluid retention in hepatic cirrhosis, ADRs including laboratory test 
abnormalities were reported in 162 out of 266 subjects (60.9%) included in the safety 
dataset of a clinical study conducted in Japan.  Common ADRs were thirst (83 events or 
31.2%) and pollakiuria (45 events or 16.9%) among others (at the time of approval of the 
new indication). 
In patients with ADPKD, ADRs including laboratory test abnormalities were reported in 
851 (including 117 Japanese) (88.6%) out of 961 (including 118 Japanese) subjects 
included in the safety dataset of a global study.  Common ADRs were thirst (677 events 
or 70.4%), pollakiuria (503 events or 52.3%), polyuria (366 events or 38.1%), headache 
(135 events or 14.0%), and polydipsia (100 events or 10.4%) among others (at the time of 
approval of the new indication). 
Refer to the latest Investigator’s Brochure (IB) for more information about the adverse 
events reported after treatment with tolvaptan in clinical studies. 
Tolvaptan has been granted multiple indications and is administered to patients with 
multiple diseases covering a wide age range.  The development of an OD tablet 
formulation to add to the conventional tablet will increase treatment options for patients 
and should improve patient adherence. 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
The same administration route, indications, and dose and regimen as those for Samsca 
tablets are expected to be granted for the tolvaptan OD tablet to be used in this study.  In 
other words, the new OD tablet will be filed under the category “1-(8) new dosage form 
of a drug under reexamination” and for the purpose of demonstrating bioequivalence with 
Samsca tablets.  With reference to the Guidelines for Bioequivalence Studies of Generic 
Products1 and the 2000 Guidebook for Approval Application for Pharmaceutical Products, 
2 a “bioequivalence study comparing (the conventional tablet administered with water) 
with (the proposed formulation administered without water)” and another 
“bioequivalence study comparing (the conventional tablet administered with water) with 
(the proposed formulation administered with water)” were planned. 
This randomized, 3-period 3-way crossover study using 2 different formulations and 2 
different dosing regimens has therefore been designed to evaluate the plasma 
pharmacokinetics and bioequivalence of the OD tablet (with water), OD tablet (without 
water), and conventional tablet administered once orally to Japanese healthy adult male 
subjects. 
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This protocol has been written generally in accordance with the Guidelines for 
Bioequivalence Studies of Generic Products. 1  The intended doses for this study (30 mg, 
15 mg) are within the approved dose range.  The selected safety endpoints and their 
evaluation time points have also been selected after due consideration.  This study will be 
conducted using hospitalized subjects so that any medical emergencies can be dealt with 
properly should they occur.  The above arrangements and considerations are considered 
adequate for the ethical and scientific conduct of this study. 
2.2 
Dosing Rationale 
2.2.1 
Regimens 
The 2000 Guidebook for Approval Application for Pharmaceutical Products2 states “For 
the application for approval of a new OD tablet following the approval of a conventional 
tablet formulation, a ‘bioequivalence study comparing (the conventional tablet 
administered with water) with (the proposed formulation administered without water)’ 
and another ‘bioequivalence study comparing (the conventional tablet administered with 
water) with (the proposed formulation administered with water)’ are in principle 
recommended to characterize the OD tablet.”  This is the reason for the intended 
regimens with and without water.  The Guidelines for Bioequivalence Studies of Generic 
Products1 stipulate “In principle, drugs are given to subjects with 100 to 200 mL water 
(normally 150 mL) after fasting for more than 10 hours.”  This is the rationale for the 
selected volume (about 150 mL) of water to be used for administration with water. 
2.2.2 
Dose Levels 
Producing the marketed tolvaptan formulation (conventional tablet) and OD tablet in the 
same tablet size necessarily results in different compositions between the tolvaptan OD 
tablets 15 mg and 30 mg.  Because of this, this study evaluates bioequivalence at each 
dose level (namely, separate comparisons between the tolvaptan OD tablet 15 mg and 
tolvaptan conventional tablet 15 mg and between the tolvaptan OD tablet 30 mg and 
tolvaptan conventional tablet 30 mg). 
2.3 
Trial Objectives 
To assess the bioequivalence of OPC-41061 OD tablets and OPC-41061 conventional 
tablets at 15 and 30 mg in healthy adult male subjects. 
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3 
Trial Design 
3.1 
Type/Design of Trial 
This single-center, open-label, randomized, 3-period 3-way, crossover study using 2 
different formulations and 2 different dosing regimens investigates bioequivalence 
between tolvaptan OD and conventional tablets in 84 healthy adult male subjects in 2 
cohorts.  Bioequivalence between the OD and conventional 15 mg tablets will be 
investigated in Cohort 1.  In Cohort 2, bioequivalence between the OD and conventional 
30 mg tablets will be investigated. 
The trial design schematic is presented in Figure 3.1-1 (applicable to both cohorts). 
This study consists of a main study and an add-on subject study in additional subjects for 
both Cohort 1 and 2.  With reference to the Guidelines for Bioequivalence Studies of 
Generic Products, 1 the add-on subject study will be conducted only once when 
bioequivalence is not demonstrated in the main study for the reason specified in Section 
7.7, Decision on Whether to Conduct an Add-on Subject Study.  Both the main study and 
add-on subject study will be conducted in the same manner with the exception of sample 
size.  When bioequivalence is demonstrated in only one of the cohorts, the add-on subject 
study will be conducted in the cohort in which bioequivalence was not demonstrated. 
Subjects will be admitted to the trial site the day before dosing in Period 1.  Subjects will 
be discharged, after blood collection for safety and pharmacokinetic evaluations, 
following the end of treatment examination in Period 3. 
Subjects will be randomly assigned to the conventional tablet first group, OD tablet with 
water first group, or OD tablet without water first group according to the randomization 
code and receive either the 15 mg conventional tablet or OD tablet in Cohort 1 and either 
the 30 mg conventional tablet or OD tablet in Cohort 2. 
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Figure 3.1-1 
Trial Design Schematic 
3.2 
Trial Treatments 
3.2.1 
Investigational Medicinal Products 
3.2.1.1 
Tolvaptan OD Tablet 
1) Administered with water 
One tolvaptan OD tablet 15 mg or 30 mg will be administered with about 150 mL 
of water under fasting conditions.  Investigational medicinal products (IMPs) will 
be administered after at least 10 hours of fasting.  Subjects will not be allowed to 
eat until 4 hours postdose.  Fluid intake will not be allowed from 2 hours before to 
2 hours after dosing, excluding water given to swallow the tablet. 
2) Administered without water 
The subject will disintegrate one tolvaptan OD tablet 15 mg or 30 mg in the 
mouth (on the tongue) under fasting conditions and promptly swallow with saliva.  
Both formulations will be administered after at least 10 hours of fasting.  Subjects 
will not be allowed to eat until 4 hours postdose.  Fluid intake will not be allowed 
from 2 hours before to 2 hours after dosing. 
3.2.1.2 
Tolvaptan Conventional Tablet 
One tolvaptan conventional tablet 15 mg or 30 mg will be administered with about 
150 mL of water under fasting conditions. 
Screening examination 
Admission 
Period 1 
Period 2 
Period 3 
[Conventional tablet first group] 
[OD tablet with water first group]
[OD tablet without water first group]
OD tablet  
with water 
OD tablet  
with water 
OD tablet  
with water 
OD tablet  
without water 
OD tablet  
without water 
OD tablet  
without water 
Conventional 
tablet 
Conventional 
tablet 
Conventional 
tablet 
[Day −28 to −2] 
[Day −1] 
[Day1 to 3] 
[Day4 to 6] 
[Day7 to 8] 
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Both formulations will be administered after at least 10 hours of fasting.  Subjects will 
not be allowed to eat until 4 hours postdose.  Fluid intake will not be allowed from 2 
hours before to 2 hours after dosing, excluding water given to swallow the tablet. 
3.2.2 
Treatment Period 
After single oral dosing in Period 1, there is a 72-hour washout period, followed by single 
oral dosing in Period 2 (different from the formulation + regimen combination in Period 
1).  After single oral dosing in Period 2, there is a 72-hour washout period, followed by 
single oral dosing in Period 3 (different from the formulation + regimen combination in 
Periods 1 and 2). 
[Rationale for treatment period and washout period] 
Treatment period:  according to the statement in the Guidelines for Bioequivalence 
Studies of Generic Products, 1 “In principle, bioequivalence studies should have a single-
dose design.” 
Washout period:  
In the single oral dose study (156-00-001), food effect study (156-00-002), and single-
dose part of the oral repeated-dose study (156-00-003) conducted in Japan, the mean 
elimination half-life of tolvaptan after administration of 30 mg was 3.89, 4.39 (in a 
fasting state), and 3.33 hours, respectively.  Guidelines for Bioequivalence Studies of 
Generic Products1 state “Washout periods should usually be more than 5 times the 
elimination half-life of the unchanged active ingredient or active metabolites to be 
measured.”  The longest reported elimination half-life in these studies was 8.5 hours 
(Study 156-00-002, Subject No. 001-0016).  At least 5 times 8.5 hours means the 
washout period should be at least 43 hours.  Plasma tolvaptan concentration at 48 hours 
postdose was below the lower limit of quantitation (5 ng/mL) in all subjects enrolled in 
the above 3 studies.  Because 2 ng/mL is being adopted as the lower limit of quantitation 
in the present study, 72 hours is selected for washout to ensure plasma tolvaptan 
concentration decreases to sufficiently low levels between doses to ensure accurate 
bioequivalence evaluation. 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Description of Population 
A total of 84 healthy adult male subjects at least 20 years and less than 40 years of age 
will be enrolled. 
Any enrolled subject who withdraws consent or is judged not to be able to receive IMP 
before the start of IMP administration will be replaced with a reserve subject. 
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Neither subject enrollment nor replacement will take place for subjects who are 
withdrawn from the trial after randomization. 
3.3.2 
Subject Selection and Numbering 
A subject identifier comprising a 3-digit trial site number, the letter “S,” and 5-digit serial 
number per trial site will be assigned to each subject (eg, “101S00001”). 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Written informed consent will be freely obtained from all subjects.  Consent will be 
documented on a written informed consent form (ICF).  The ICF will be approved by the 
same institutional review board (IRB) that approves this protocol. 
Each ICF will comply with the ICH (International Conference on Harmonisation) Good 
Clinical Practice (GCP) Guideline3 and local regulatory requirements. 
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent.  However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care. 
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator, the IRB approved written ICF will 
be signed and dated by both the subject and the person obtaining consent (investigator).  
If a study coordinator has provided a supplemental explanation, the IRB approved written 
ICF will be signed and dated by the study coordinator.  The subject will receive a copy of 
the signed ICF; the original shall be kept on file by the investigator. 
Subjects may be asked to sign additional ICFs if the protocol is amended to significantly 
add or change procedures. 
3.4.2 
Inclusion Criteria 
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1. 
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Table 3.4.2-1 
Inclusion Criteria 
1. 
Japanese males at least 20 years and less than 40 years of age at the time of informed consent 
2. 
Body weight of at least 50.0 kg 
3. 
BMI [body weight in kg / (height in m)2] of at least 17.6 kg/m2 and less than 25.0 kg/m2 
4. 
Judged by the investigator or subinvestigator to be capable of providing written informed consent 
prior to the start of any trial-related procedures and capable of complying with the trial procedures 
for this study. 
 
 [Rationale for inclusion criteria] 
1 
The lower age limit is set so that only adults are enrolled.  The upper limit of 40 is selected 
because the risk of other complicating diseases increases with age and also because older 
individuals may have reduced metabolic capacity.  Only males are to be enrolled because males 
do not become pregnant or menstruate, both of which may affect study procedures. 
2 
This criterion is to ensure appropriate pharmacokinetic and safety evaluations. 
3 
This criterion is to restrict inter-individual variability due to obesity in pharmacokinetics in 
subjects. 
4 
This criterion is for ethical considerations. 
 
3.4.3 
Exclusion Criteria 
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1. 
Table 3.4.3-1 
Exclusion Criteria 
1. 
Judged by the investigator, subinvestigator, or sponsor to have a clinically significant abnormality 
in results of the screening examination (including a notable deviation from the site’s standard 
values) or a medical history that could place the subject at risk or affect the evaluation of drug 
absorption, distribution, metabolism, or excretion. 
Examples include, but are not limited to, a history or current medical conditions related to the heart, 
liver, kidneys, nervous system, stomach and intestines, respiratory organs, blood, or immune 
system. 
2. 
History of alcohol or drug dependence or abuse within 2 years prior to the trial 
3. 
History or current symptoms of hepatitis or acquired immunodeficiency syndrome (AIDS) or 
positive test results for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), or 
human immunodeficiency virus (HIV), or judged to have syphilis based on the results of 
Treponema pallidum (TP) antibody test or rapid plasma reagin (RPR) test 
4. 
History of any severe drug allergy 
5. 
Positive results in alcohol screening test or urine drug screening test at time of screening 
examination 
6. 
Prior experience of blood collection difficulties 
7. 
Use of any other IMP within 120 days prior to Period 1 IMP administration 
8. 
Blood collection (eg, donation) of > 200 mL within 30 days, > 400 mL within 90 days, or 1200 mL 
within 1 year prior to Period 1 IMP administration 
9. 
Consumption of any food or beverage containing St. John’s wort within 14 days prior to Period 1 
IMP administration 
10. 
Consumption of any food or beverage containing grapefruit, Seville orange, or star fruit within 7 
days prior to Period 1 IMP administration 
11. 
Use of any prescribed drug, over-the-counter (OTC) drug, Chinese herbal medicine, or vitamin 
supplement within 14 days prior to Period 1 IMP administration 
12. 
Use of tobacco products within 60 days prior to Period 1 IMP administration, or positive urine 
cotinine test at screening. 
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Table 3.4.3-1 
Exclusion Criteria 
13. 
Occupational exposure to insecticides or organic solvents within 30 days prior to the trial 
14. 
A blood pressure measurement after at least 3 minutes of rest that deviates from the institutional 
reference range 
15. 
A pulse rate measurement after at least 3 minutes of rest that deviates from the institutional 
reference range 
16. 
History of severe bleeding or bleeding tendency 
17. 
Sexually active males who are not capable of or do not agree to practice 2 different methods of 
birth control or remain abstinent during the trial and for 30 days after the last dose of IMP. 
If employing birth control, 2 of the following methods must be used:  vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device, birth control pill, or condom with spermicide. 
18. 
History of serious mental disorders 
19. 
Seeing or is scheduled to see a doctor at another hospital or clinical department during the trial 
20. 
Judgment by the investigator or subinvestigator that the subject should not participate in the study 
for any other reason 
 
[Rationale for exclusion criteria] 
1 to 6 
These criteria are set as safety precautions. 
7 
This criterion is set to define a period during which participation in a clinical study is 
generally inappropriate. 
8 
This criterion is set based on the standards for blood donation established by the New 
Blood Program Advisory Committee. 
9 to 13 
These criteria are set to prevent unintended effects on pharmacokinetics. 
14 to 20 
These criteria are for safety precautions. 
 
Re-entry of individuals judged to be ineligible based on the screening examination is not 
allowed.  If the investigator or subinvestigator decides to perform a retest (eg, clinical 
laboratory test), the retest must be documented in accordance with the trial site’s 
procedure. 
3.5 
Variables 
3.5.1 
Bioequivalence 
3.5.1.1 
Primary Variable 
AUCt and Cmax of tolvaptan 
3.5.1.2 
Reference Variables 
1) Plasma concentration-time profile of tolvaptan 
2) AUC∞, MRT∞, tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, and tlast of 
tolvaptan 
3) By-subject ratios of AUCt, Cmax, AUC∞, MRT∞, and λz of tolvaptan for 
administration of OD tablet with and without water to those for administration of 
conventional tablet 
4) Difference (value for OD tablet minus value for conventional tablet) in tmax by 
subject between administration of OD tablet without water and administration of 
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conventional tablet and between administration of OD tablet with water and 
administration of conventional tablet 
3.5.2 
Safety 
Body weight, vital signs (body temperature, blood pressure, and pulse rate), clinical 
laboratory tests, 12-lead ECG, physical examination, and adverse events 
3.6 
Measures to Minimize/Avoid Bias 
The sponsor will prepare the randomization code.  Subjects are randomized to 3 groups in 
each cohort according to the randomization code. 
No bias will occur, even without blinding, because AUCt and Cmax values based on 
plasma drug concentration will be used for evaluation in this study.  This is the reason for 
selecting the open-label design. 
3.7 
Trial Procedures 
Trial procedures and assessment time points are summarized in Figure 3.7-1 and Table 
3.7-1, respectively (same across the cohorts).  
 
Figure 3.7-1 
Trial Procedures 
 
Day −28 to −2 
Day before 
IMP 
administra-
tion 
Day of IMP 
administration 
Washout period (72 hours) 
Day of IMP 
administration 
Day of IMP 
administration
Day after IMP 
administration 
Day after IMP 
administration 
Day after IMP 
administration 
Day before 
IMP 
administration 
Screening period 
Treatment period 
Day before 
IMP 
administration 
Period 1 
Period 2 
Period 3 
Informed consent and 
eligibility assessment
Washout period (72 hours)
Admission and examination
on the day before IMP
administration for Period 1
Randomization and IMP 
administration
Period 1 end of 
treatment examination
Examination on the day
before IMP administration
for Period 2
IMP administration
Period 2 end of 
treatment examination
Examination on the day
before IMP administration
for Period 3
IMP administration
Period 3 end of treatment 
examination and discharge
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Table 3.7-1 
Schedule of Assessments 
 
Day −28 
to −2 
Day −1, 3, 
and 6 
Day 1, 4, and 7 
Day 2, 5, and 8 
At 
Discon-
tinuation 
Predose 
0 h 
1 h 
2 h 
3 h 
4 h 
5 h 
6 h 
8 h 
10 h 
12 h 
16 h 
24 h 
Informed consent 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Body weight 
○a 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
○ 
Blood collection for 
plasma concentration 
measurement 
 
 
○ 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
Physical examination 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
○ 
Vital signs 
○ 
○ 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
○ 
○ 
Clinical laboratory test 
○ 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
○ 
Immunological test 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine alcohol, drug, 
cotinine tests 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
○ 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
○ 
○ 
Randomization 
 
 
○c 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications/therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission/Discharge 
Visit 
Admissionb 
 
 
 
 
 
 
 
 
 
 
 
 
Discharged 
 
a:  Height is measured only from Day −28 to −2. 
b:  Only on Day −1 (Subjects will continue to be hospitalized on Day 3 and 6 from Day −1.) 
c:  Only on Day 1 
d:  The subject will be discharged only on Day 8, not on Day 2 or 5. 
 
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3.7.1 
Schedule of Assessments (Both Cohorts) 
3.7.1.1 
Screening 
After informed consent, the subject will undergo the examinations and tests specified 
below within 28 days prior to IMP administration in Period 1 (between Day −28 and −2) 
for eligibility assessment.  Enrolled subjects and reserve subjects will be selected from 
qualified subjects.  Test results (with the eligibility assessment) will be documented in 
medical records together with the reason for an “ineligible” assessment. 
Tests and Examinations 
Time Point(s) and 
Acceptable Time Window 
Height, body weight, BMI (weight will be measured in a fasting 
state) 
Height will be measured to 0.1 cm.  BMI will be calculated (to one 
decimal place) from the height and body weight measured at 
screening using the equation below. 
Equation:  BMI = Body weight (kg) / {Height (m)}2 
Between 28 and 2 days 
before IMP administration in 
Period 1 
Subject demographics 
(Birth date, sex, race, ethnicity, medical history, current symptoms, 
drinking habit, smoking habit) 
Physical examination 
Vital signs (body temperature, blood pressure, pulse rate) 
Clinical laboratory test (blood and urine collection) 
Immunological test (HBsAg, HCV antibody, HIV antigen/antibody, 
TP antibody, and RPR test) 
Urine alcohol, drug, and cotinine tests 
12-lead ECG 
Adverse events 
Concomitant medications/therapy and restricted foods specified in 
Restrictions after informed consent 
 
3.7.1.2 
Day Before IMP Administration in Period 1 (Day −1) 
Each enrolled subject and reserve subject will visit the trial site in the afternoon the day 
before IMP administration in Period 1 (Day −1) and be asked to reconfirm his consent.  
Subsequently, he will undergo the observations, tests, and examinations listed below for 
eligibility assessment and be admitted when judged to be eligible.  The subject will have 
dinner at around 1900 and fast from 2200. 
Tests and Examinations 
Time Point(s) and 
Acceptable Time Window 
Physical examination 
As appropriate 
Vital signs (body temperature, blood pressure, pulse rate) 
Adverse events 
Concomitant medications/therapy and restricted foods specified in 
Restrictions 
 
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3.7.1.3 
Day Before IMP Administration in Periods 2 and 3 (Day 3 and 6) 
Subjects who have completed the preceding Period will be enrolled in next Period.  In the 
morning the day before IMP administration (Day 3 or 6), each subject will undergo the 
same observations, tests, and examinations as those on Day −1 for eligibility assessment.  
The subject will have dinner at around 1900 and fast from 2200. 
3.7.1.4 
Day of IMP Administration (Day 1, 4, and 7) 
3.7.1.4.1 
Before IMP Administration 
The subject will undergo the observations, tests, and examinations listed below. 
Tests and Examinations 
Time Point(s) and 
Acceptable Time Window 
Body weight 
Within 3 hours before IMP 
administration 
Physical examination 
Vital signs (body temperature, blood pressure, pulse rate) 
Blood collection for plasma drug concentration measurement (before 
dosing on the day of IMP administration) 
Clinical laboratory test (blood and urine collection) 
12-lead ECG 
Adverse events 
Concomitant medications/therapy and restricted foods specified in 
Prohibited Medications 
 
3.7.1.4.2 
Subject Enrollment and Treatment Assignment (Only on Day 
1) 
Subjects will be randomized per cohort.  Enrolled subjects will be randomly assigned to 
the conventional tablet first group, OD tablet with water first group, or OD tablet without 
water first group according to the randomization code, in ascending order of subject 
identifier. 
3.7.1.4.3 
Subject Replacement (Only on Day 1) 
Each enrolled subject who withdraws consent or is judged not to be able to receive IMP 
before the start of IMP administration will be replaced with a reserve subject. 
Neither subject enrollment nor replacement will take place for discontinued subjects after 
IMP administration. 
3.7.1.4.4 
IMP Administration 
The subject will receive the IMP once orally at about 0900 and swallow with about 
150 mL of water or saliva (without water).  The exact time of administration in individual 
subjects should be adjusted for subsequently scheduled blood collection and tests.  The 
IMP will be administered after at least 10 hours of fasting.  Fluid intake will not be 
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allowed from 2 hours before to 2 hours after dosing.  Except for that period, subjects will 
be allowed to intake fluids freely.  Eating will not be allowed for 4 hours after dosing. 
3.7.1.4.5 
After IMP Administration 
Subjects who did not receive the IMP will be discharged from the trial site. 
Subjects who remain at the site will undergo the observations, tests, and examinations 
listed below.  They will receive lunch at about 1300 and dinner at about 1900. 
Tests and Examinations 
Time Point(s) (hours after dosing) 
Acceptable Time 
Window 
Blood collection for plasma 
concentration measurement 
1, 2, 3, 4, 5, 6, 8, 10, 12 
±5 minutes 
Vital signs (body temperature, 
blood pressure, pulse rate) 
2 
±30 minutes 
Adverse events 
As appropriate 
− 
Concomitant 
medications/therapy and 
restricted foods specified in 
Prohibited Medications 
As appropriate 
− 
 
3.7.1.5 
Day After IMP Administration (Day 2, 5, and 8) 
Subjects will undergo the observations, tests, and examinations listed below. 
Observations, Tests, and 
Examinations 
Time Point(s) (hours after dosing) 
Acceptable Time 
Window 
Blood collection for plasma 
concentration measurement 
16 
±5 minutes 
Body weight 
24 
Within 60 minutes after 
the scheduled time (after 
awakening) 
Physical examination 
24 
±60 minutes 
Vital signs (body temperature, 
blood pressure, pulse rate) 
24 
±60 minutes 
Clinical laboratory test (blood 
and urine collection) 
24 
±60 minutes (urine may be 
collected from 
immediately after 
awakening) 
12-lead ECG 
24 
±60 minutes 
Adverse events 
As appropriate 
− 
Concomitant 
medications/therapy and 
restricted foods specified in 
Prohibited Medications 
As appropriate 
− 
 
3.7.1.6 
At Discontinuation 
Each subject who is withdrawn from the trial after IMP administration in Period 1 will 
undergo the observations, tests, and examinations shown in the table below.  No all of the 
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procedures are to be mandatory if not feasible (eg, when the subject refuses to undergo 
the procedures specified for discontinuation or there is a medical emergency affecting the 
subject at that time).  Also, the same procedures the subject has undergone on the day of 
trial discontinuation may be omitted. 
Observations, Tests, and Examinations 
Time Point(s) and 
Acceptable Time Window 
Body weight 
At discontinuation 
Physical examination 
Vital signs (body temperature, blood pressure, pulse rate) 
Clinical laboratory test (blood and urine collection) 
12-lead ECG 
Adverse events 
Concomitant medications/therapy and restricted foods specified in 
Restrictions 
 
3.7.1.7 
Follow-up Examination 
Subjects with adverse events unresolved at the end-of-trial examination or at the time of 
withdrawal will be followed up according to Section 5.7, Follow-up of Adverse Events. 
3.7.2 
Safety Assessments 
3.7.2.1 
Adverse Events 
Refer to Section 5, Reporting of Adverse Events.  
3.7.2.2 
Clinical Laboratory Assessments 
The clinical laboratory data specified in Table 3.7.2.2-1 will be collected at scheduled 
time points.  The date and time of each blood and urine collection will be recorded in 
source documents and in the case report form (CRF). 
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Table 3.7.2.2-1 
Clinical Laboratory Assessments 
Hematology 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC count with differentials (neutrophil, 
lymphocyte, monocyte, basophil, eosinophil) 
Platelet count 
Hemoglobin 
Hematocrit 
Serum Chemistry: 
Aspartate Aminotransferase (AST) 
Alanine Aminotransferase (ALT) 
Alkaline Phosphatase (ALP) 
Lactic Dehydrogenase (LDH) 
Gamma Glutamyl Transferase (GGT)  
Protein, total 
Albumin 
Bilirubin, total 
Cholesterol, total 
Triglycerides 
Glucose 
Blood urea nitrogen (BUN) 
Creatinine 
Uric acid 
Creatine phosphokinase (CPK) 
Serum electrolytes (sodium, potassium, chloride, 
calcium) 
Urinalysis 
Blood 
Glucose 
pH 
Protein 
Specific gravity 
Sediments 
Bilirubin 
Urobilinogen 
Ketone body 
 
3.7.2.3 
Physical Examination and Vital Signs (Body Temperature, 
Blood Pressure, Pulse Rate) 
3.7.2.3.1 
Physical Examination 
The subject is to undergo an examination at the scheduled time points and physical 
findings are to be recorded.  The head, ears, eyes, nose and pharynx, chest, abdomen, 
urogenital organs, limbs, nervous system, and skin and mucosa are examined individually.  
The investigator or subinvestigator will be responsible for evaluating physical findings.  
Whenever possible, physical examinations in each subject will be performed by the same 
clinician. 
The date and time of examination and observed physical findings will be documented in 
source documents and the CRF. 
When clinically significant physical findings not seen at the baseline examination are 
observed after IMP administration, they will be documented as adverse events and 
followed up until a stable outcome is achieved. 
3.7.2.3.2 
Vital Signs (Body Temperature, Blood Pressure, Pulse Rate) 
Vital signs will be measured at scheduled time points. 
1) Body temperature 
Axillary temperature will be measured in tenths of a degree Celsius and documented 
together with the date and time of measurement in source documents and the CRF. 
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2) Blood pressure (diastolic and systolic), pulse rate 
Blood pressure and pulse rate will be measured after the subject has rested in the sitting 
position for at least 3 minutes and documented together with the date and time of 
measurement in source documents and the CRF. 
3.7.2.4 
Electrocardiogram Assessments 
A 12-lead electrocardiogram will be obtained at scheduled time points after the subject 
has rested in the supine position for at least 5 minutes.  Heart rate, RR interval, PR 
interval, QRS interval, QT interval, and corrected QT interval (Fridericia’s correction, 
QTcF; Bazett’s formula, QTcB) will be measured.  The investigator or subinvestigator 
will evaluate the ECG data and documents them together with the date and time of 
measurement, normal/abnormal assessment, and other findings in source documents and 
the CRF. 
3.7.2.5 
Body Weight 
The subject’s body weight will be measured to 0.1 kg at scheduled time points.  The body 
weight value will be documented together with the date and time of measurement in 
source documents and the CRF. 
3.7.3 
Pharmacokinetic Assessments 
3.7.3.1 
Time Points 
Cohort 1 and 2:  Before IMP administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours 
postdose in each period 
[Rationale for blood collection time points] 
A single oral dose study (156-00-001), food effect study (156-00-002), oral repeated-dose 
study (156-00-003), and food effect study using the finished product (156-07-002) have 
been completed in Japan.  In these studies, the mean tmax and mean elimination half-life 
were 2.18 to 3.21 hours and 3.33 to 4.39 hours, respectively, after dosing of 15 mg and 
30 mg tablets.  The studies also reported the linearity of tolvaptan pharmacokinetics 
(excluding Cmax) in the dose range of 5 to 480 mg, 4 suggesting a similar half-life for the 
15 mg and 30 mg tablets.  The time period at least 3 times the sum of tmax + elimination 
half-life, calculated based on the data from the above 4 studies (as recommended for 
calculation of a biological fluid sampling time point in the Guidelines for Bioequivalence 
Studies of Generic Products1) was not less than 16 hours.  Based on the above, the 11 
time points (immediately before dosing, 4 points around the tmax [1, 2, 3, and 4 hours 
postdose], and 6 points in the elimination phase [5, 6, 8, 10, 12, and 16 hours postdose] 
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were selected for each period with reference to the Guidelines for Bioequivalence Studies 
of Generic Products. 1 
3.7.3.2 
Blood Collection Procedure and Sample Treatment 
About 4 mL of blood will be drawn each time from a vein and collected in a sodium 
heparin tube.  The date and time of each blood collection will be recorded in source 
documents and the CRF. 
After collection, the tube will be gently inverted a few times and placed in ice water.  
Then the sample will be immediately (within 45 minutes after collection) centrifuged at 
about 4°C and about 1710 × G for about 10 minutes.  The separated plasma will be 
divided into 2 polypropylene sample tubes in nearly equal volumes and frozen at −15°C 
or lower within about 90 minutes after separation.  A sample label on which essential 
information (protocol number, subject identifier, time of sampling, etc.) is entered at the 
trial site will be affixed to each plasma sample tube. 
3.7.3.3 
Transportation 
Plasma samples will be kept frozen with dry ice and sent to the bioanalytical laboratory.  
Two samples obtained at one time point from one subject will be sent in separate 
shipments to the bioanalytical laboratory. 
3.7.3.4 
Plasma Drug Concentration Measurement 
Plasma tolvaptan concentration will be determined at the bioanalytical laboratory 
according to the validated procedure at the laboratory. 
3.7.3.5 
Reporting of Measurement Results 
The bioanalytical laboratory will retain the source documents of plasma drug 
concentration measurements.  The sponsor will keep the copy of electronic file of plasma 
drug concentration measurements submitted by the bioanalytical laboratory. 
3.7.3.6 
Handling of Remaining Samples 
The bioanalytical laboratory will keep remaining samples frozen and dispose of them 
after completion of the clinical study report. 
3.7.4 
End of Trial 
The end of trial date is defined as the day on which the last subject completes the trial. 
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3.8 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.8.1 
Entire Trial 
If the sponsor terminates or suspends the trial for safety or any other unexpected reason, 
prompt notification will be given to the head of the trial site and regulatory authorities in 
accordance with regulatory requirements. 
3.8.2 
Individual Site 
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB if judged to be necessary for medical, safety, regulatory, ethical or other reasons 
consistent with applicable laws, regulations, and GCP.  The head of the trial site will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB at the 
site. 
3.8.3 
Individual Subject Discontinuation 
3.8.3.1 
Treatment Discontinuation 
After IMP administration, a subject may stop treatment permanently for a variety of 
reasons.  Treatment discontinuations may be initiated by a subject or may become 
medically necessary due to adverse events (AEs), required treatment with a disallowed 
medication or therapy, or other issues, as determined by the investigator.  The 
discontinued subject should be encouraged to undergo the examinations specified for 
discontinuation. 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation 
All subjects have the right to withdraw their consent from further participation in the trial 
at any time.  The investigator can also discontinue a subject’s participation in the trial at 
any time if medically necessary.  The subject’s participation in the trial must be 
terminated when any of the following applies: 
 Reasons related to AE: 
 Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard 
 Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP) 
 Serious adverse event (SAE)  
 Other potentially IMP-related safety concerns or AEs 
 Death 
 Reasons unrelated to medical condition (provide detail and review AE history with 
subject) 
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 Withdrawal of informed consent (complete written withdrawal of consent form) 
 Lost to follow-up 
 Termination of all or part of the trial by the sponsor 
 
If the subject (temporarily interrupts or) discontinues IMP due to an AE, the investigator 
will follow the event until it has resolved or stabilized according to Section 5.7, Follow-
up of Adverse Events. 
3.8.3.3 
Withdrawal of Consent 
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice.  Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent.  
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject who withdraws consent should be encouraged to undergo the examinations 
specified for discontinuation. 
3.9 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on treatment. 
Subjects who sign an ICF but who are not started on treatment are permitted to be re-
screened.  In the event that the subject is re-screened for trial participation, and the re-
screening is not completed within the original screening window, a new ICF must be 
signed. 
3.10 
Definition of Completed Subjects 
The treatment period is defined as the time period during which the subject is evaluated 
for primary and/or reference objectives of the trial irrespective of whether or not the 
subject received all doses of the IMP.  Subjects who undergo the last scheduled 
evaluation during the treatment period will be defined as trial completers.  For purposes 
of this trial, subjects who complete the evaluation in Period 3 will be defined as trial 
completers. 
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3.11 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted after discharge in Period 3 will be classified as “lost to 
follow-up.” 
The investigator or designee will make 3 documented attempts to contact the subject by 
telephone and in the event the site is unable to reach the subject by telephone, the site will 
attempt to contact the subject via certified mail or an alternative similar method, where 
appropriate, before assigning a “lost to follow-up” status. 
3.12 
Subject Compliance 
The subject should be under the supervision of the investigator during the trial.  The 
investigator will guide the subject so that the subject complies with the restrictions 
specified in Section 4, Restrictions. 
3.13 
Protocol Deviations 
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor at 
the earliest possible time by telephone.  The investigator and sponsor will come as 
quickly as possible to a joint decision regarding the subject’s continuation in the trial.  
This decision will be documented by the investigator and the sponsor, and reviewed by 
the site monitor. 
4 
Restrictions 
4.1 
Prohibited Medications 
If the subject uses any drug other than the IMP between the time of consent and the end 
of treatment examination in Period 3 or discontinuation, the name, purpose of use, 
regimen, dose, route, and start and end dates (and time if possible) will be documented in 
source documents and the CRF.  If the subject undergoes any non-drug therapy during 
the same period, its name, purpose, and start and stop dates will be also documented in 
source documents. 
When the subject needs a prohibited drug or therapy to eliminate immediate hazards to 
the subjects (eg, for the treatment of AEs), the subject is to terminate the trial according 
to Section 3.8.3, Individual Subject Discontinuation. 
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Prohibited medication/therapy 
Restricted period 
Any prescription and OTC drug other than 
the IMP 
Between 14 days before IMP administration 
in Period 1 and discharge in Period 3 
Any non-drug therapy 
During hospitalization 
 
4.2 
Other Restrictions 
4.2.1 
Subject Admission 
The subject will be hospitalized between the day before IMP administration in Period 1 
and the day after IMP administration in Period 3 (8 nights and 9 days). 
4.2.2 
Self Care 
The subject will be instructed to avoid strenuous exercises, excessive eating and drinking, 
and irregular hours such as staying up late during participation in the trial. 
4.2.3 
Restricted Foods 
 The table below specifies the food products not allowed to be taken by subjects, 
together with the applicable periods of restriction. 
Food 
Restricted period 
Any food/beverage containing 
methylxanthine 
During hospitalization 
Any food/beverage containing alcohol 
Between 3 days before IMP administration in 
Period 1 and discharge in Period 3 
Any food/beverage containing St. John’s wort 
Between 14 days before IMP administration 
in Period 1 and discharge in Period 3 
Any food/beverage containing grapefruit, 
Seville orange, or star fruit 
Between 7 days before IMP administration in 
Period 1 and discharge in Period 3 
Smoking 
Between 60 days before IMP administration 
in Period 1 and discharge in Period 3 
 The subject will be allowed to take only permitted foods/beverages during 
hospitalization. 
 During hospital stay, the subject will have breakfast (not served on the day of 
IMP administration), lunch, and dinner at about 0900, 1300, and 1900, 
respectively, each day.  The same foods/beverages will be served to all subjects.  
When a scheduled test/blood collection conflicts with a meal, the subject will 
undergo the test/blood collection first. 
 Eating will not be allowed between 10 hours before and 4 hours after IMP 
administration in each period. 
 Fluid intake will not be allowed from 2 hours before to 2 hours after IMP 
administration in each period.  Except for that period, subjects will be allowed to 
intake fluids freely. 
 For each clinical laboratory test (excluding the tests scheduled the same day as 
IMP administration), eating will not be allowed from 2200 the day before to 
blood/urine collection. 
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4.2.4 
Prohibition of the Supine Position 
The subject will not be allowed to assume the supine position, excluding when it is 
necessary for an observation/test/examination, for at least 4 hours after IMP 
administration. 
5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as a 
symptom at screening for pre planned procedures for which the underlying condition was 
known and no worsening occurred.  An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. 
An SAE includes any event that results in any of the following outcomes: 
 Death 
 Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death. 
 Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions. 
 Requires in-patient hospitalization or prolongs hospitalization. 
 Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported. 
 Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs. 
 Congenital anomaly/birth defect. 
 Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or 
convulsions that do not result in hospitalization, or the development of drug 
dependency or drug abuse. 
 
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Nonserious adverse events are all AEs that do not meet the criteria for a “serious” AE. 
Immediately Reportable Event (IRE): 
 Any SAE. 
 Any AE related to occupational exposure. 
 Potential Drug Induced Liver Injury (DILI) case (see Section 5.4).  
 Pregnancies in partners of male subjects are also defined as IREs.  Although 
normal pregnancy is not an AE, it will mandate IMP discontinuation and must be 
reported on an IRE form to the sponsor.  Pregnancy will only be documented on 
the AE CRF if there is an abnormality or symptom. 
 
Clinical Laboratory Test Value Changes:  It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available.  This review will be 
documented by the investigator’s dated signature on the laboratory report.  For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject.  This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed.  The investigator 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 (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. 
 
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5.2 
Eliciting and Reporting Adverse Events 
The investigator will periodically assess subjects for the occurrence of AEs.  To avoid 
bias in eliciting AEs, subjects should be asked the non-leading question:  “How have you 
felt since your last visit?”  All AEs (serious and nonserious) reported by the subject must 
be recorded on the source documents and CRFs provided by the sponsor.  Serious AE 
collection is to begin after a subject has signed the ICF and end at the time of discharge. 
Use medical terminology in AE reporting.  Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms.  Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition. 
A reported AE that undergoes a change in severity, seriousness, or toxicity should be 
reported as a new AE on the CRF. 
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3.  Special attention should 
be paid to recording hospitalization and concomitant medications. 
5.3 
Immediately Reportable Events  
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, AE related to occupational exposure, DILI, or confirmed 
pregnancy, by telephone, fax, or e-mail to the sponsor using the contact information on 
the cover page of this protocol.  An IRE form must be completed and sent by e-mail to 
the sponsor.  (Please note that the IRE form is NOT the AE CRF.)  
Subjects experiencing SAEs should be followed clinically until the events are resolved, 
stabilized, or the subject is lost to follow-up.  Resolution means that the subject has 
returned to the baseline state of health and stabilized means that the investigator does not 
expect any further improvement or worsening of the subject’s condition.  It is expected 
that the investigator will provide or arrange appropriate supportive care for the subject 
and will provide prompt updates on the subject’s status to the sponsor. 
5.4 
Potential Drug-Induced Liver Injury 
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is 3 times the upper limit of normal (ULN), a total 
bilirubin level should also be evaluated.  If the total bilirubin is 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the CRF. 
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5.5 
Pregnancy 
Women of child-bearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 
12 months). 
For men who are sexually active with partners of child-bearing potential, there must be a 
documented agreement that the subject and/or their partner will take effective measures 
(ie, double-barrier method) to prevent pregnancy during the course of the trial and for 
30 days after the last dose of IMP.  Unless the subject is sterile (ie, women who have had 
a bilateral oophorectomy and/or hysterectomy or who have been postmenopausal for at 
least 12 consecutive months; or men who have had a bilateral orchidectomy) or remains 
abstinent, 2 of the following precautions must be used:  vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth control pills, or condom with spermicide.  Any 
single method of birth control, including vasectomy and tubal ligation, may fail, leading 
to pregnancy.  The contraceptive method will be documented at each trial visit. 
During the trial, all subjects should be instructed to contact the investigator immediately 
if they suspect their partners might be pregnant (eg, missed or late menstrual cycle). 
The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure during the trial and for 30 days after the last dose of IMP, and record the 
event on the IRE form and forward it to the sponsor.  The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy.  
The investigator must report to the sponsor, on appropriate Pregnancy Surveillance 
Form(s), follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome.  Infants will be followed for a minimum of 6 months 
from the date of birth. 
5.6 
Procedure for Breaking the Blind 
Not applicable. 
5.7 
Follow-up of Adverse Events 
For this trial, information on AEs will be followed up until discharge in Period 3. 
5.7.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE CRF with the current status noted.  If a subject has an AE or has not recovered from 
an AE at the last scheduled contact, follow-up contacts will be scheduled at least every 
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4 weeks until the event is resolved, stabilized, or the subject is lost to follow-up.  All 
nonserious events that are ongoing at the last scheduled contact will be recorded as 
ongoing on the CRF.  For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested to further 
ascertain causality (including, but not limited to, information such as risk-related 
behavior, family history and occupation).  The follow-up information after the last 
scheduled contact will be recorded in the subject’s medical record. 
5.7.2 
Follow-up of Serious Adverse Events 
This trial requires that subjects be actively monitored for SAEs up to discharge in Period 
3. 
Serious AEs that are identified or ongoing at the last scheduled contact must be 
recorded on the AE CRF page and reported to the sponsor according to the reporting 
procedures outlined in Section 5.3.  All SAEs that are ongoing at the last scheduled 
contact will be recorded as ongoing on the CRF. 
This may include unresolved previously reported SAEs, or new SAEs.  The 
investigator will follow SAEs until the events are resolved, stabilized, or the subject is 
lost to follow-up.  The investigator will continue to report any significant follow-up 
information to the sponsor until the event is resolved, stabilized, or the subject is lost to 
follow-up with the IRE form. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring 
After Last Scheduled Contact 
Any new SAEs reported by the subject to the investigator that occur after the last 
scheduled contact, and are determined by the investigator to be reasonably associated 
with the use of the IMP, should be reported to the sponsor.  This may include SAEs that 
are captured on follow-up telephone contact or at any other time point after the defined 
trial period (ie, up to last scheduled contact).  The investigator should follow SAEs 
identified after the last scheduled contact until the events are resolved, stabilized, or the 
subject is lost to follow-up.  The investigator should continue to report any significant 
follow-up information to the sponsor until the event is resolved, stabilized, or the subject 
is lost to follow-up with the IRE form. 
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6 
Pharmacokinetic/pharmacodynamic Analysis 
6.1 
Pharmacokinetic Analysis 
6.1.1 
Primary Variables 
AUCt and Cmax of tolvaptan 
6.1.2 
Reference Variables 
1) Plasma concentration-time profile of tolvaptan 
2) AUC∞, MRT∞, tmax, λz, AUC_%Extrap, t1/2,z, CL/F, CL/F/BW, and tlast of 
tolvaptan 
3) By-subject ratios of AUCt, Cmax, AUC∞, MRT∞, and λz of tolvaptan for 
administration of OD tablet with and without water to those for administration of 
conventional tablet 
4) Difference (value for OD tablet minus value for conventional tablet) in tmax by 
subject between administration of OD tablet without water and administration of 
conventional tablet and between administration of OD tablet with water and 
administration of conventional tablet 
 
6.1.3 
Datasets for Analysis 
The datasets for analysis are the same as that specified in Section 7.2.2, Bioequivalence 
Analysis Set. 
6.1.4 
Calculations of PK Parameters 
1) AUCt, Cmax, AUC∞, MRT∞, tmax, λz, AUC_%Extrap, t1/2,z, tlast, and CL/F are to 
be calculated per subject by non-compartmental analysis. 
2) Actual time after each IMP administration will be used in the calculations. 
3) The value 0 will be imputed for each plasma drug concentration measurement 
below the lower limit of quantitation in the calculations of PK parameters and 
descriptive statistics.  For calculation of λz from each blood sampling time point 
after tmax, a measurement below the lower limit of quantitation will be treated as 
missing. 
4) CL/F/BW is to be calculated by dividing CL/F by body weight (kg) before IMP 
administration in each period. 
5) The ratio between the formulations and regimens is to be calculated per parameter 
in each subject by [Value after dosing of OD tablet without water] / [Value after 
dosing of conventional tablet] and [Value after dosing of OD tablet with water] / 
[Value after dosing of conventional tablet] (parameters, AUCt, Cmax, AUC∞, 
MRT∞, and λz). 
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6) Differences in tmax ([tmax after dosing of OD tablet without water] − [tmax after 
dosing of conventional tablet] and also [tmax after dosing of OD tablet with water] 
− [tmax after dosing of conventional tablet]) are to be calculated per subject. 
 
6.1.5 
Calculation of Descriptive Statistics 
Descriptive statistics of the parameter specified in 1) of Section 6.1.2 are to be calculated 
per blood sampling time point by cohort and regimen (conventional tablet, OD tablet 
without water, and OD tablet with water).  For each parameter listed in 2) of Section 
6.1.2, descriptive statistics are to be calculated by cohort and regimen (conventional 
tablet, OD tablet without water, and OD tablet with water). 
6.2 
Pharmacodynamic Analysis 
No pharmacodynamic analysis is planned. 
7 
Statistical Analysis 
7.1 
Sample Size 
With reference to the Guidelines for Bioequivalence Studies of Generic Products, 1 the 
sample size for this study was calculated as the number of subjects required to 
demonstrate that the 90% confidence intervals of the geometric mean ratios of the AUCt 
and Cmax of tolvaptan (OD tablet without water vs conventional tablet and OD tablet with 
water vs conventional tablet) fall inside the bioequivalence range of ln(0.8) to ln(1.25). 
Of the prior crossover studies of tolvaptan in healthy adults, Study 156-00-002 reported 
the largest intra-individual variability (AUCt and Cmax, 0.033 and 0.056, respectively).  
Sample size calculation was performed using the method proposed by Diletti, et al. 
(1991) 5 based on the Cmax, in which intra-individual variability was large. 
When the ratio of the expected Cmax with the tolvaptan OD tablet (administered with or 
without water) to that with the tolvaptan conventional tablet is assumed to be 1.05, at 
least 12 subjects per group are required to achieve a power of at least 90%.  To account 
for withdrawals and dropouts, the sample size for this study was set to 14 subjects per 
group for 1 cohort, for a total of 42 subjects. 
7.2 
Datasets for Analysis 
7.2.1 
Safety Analysis Set 
The safety analysis set will include all subjects that were administered at least one dose 
of IMP. 
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7.2.2 
Bioequivalence Analysis Set 
The bioequivalence analysis set will include all subjects with both AUCt and Cmax values 
across Period 1, 2, and 3. 
7.3 
Handling of Missing Data 
Missing values will not be imputed. 
7.4 
Primary and Reference Endpoint Variables 
The following analyses will be performed for the bioequivalence analysis set per cohort. 
7.4.1 
Primary Variable Analysis 
1) For the AUCt and Cmax of tolvaptan, data will be log-transformed and analysis of 
variance (ANOVA) will be performed using group (group receiving conventional 
tablet first, group receiving OD tablet without water first, and group receiving 
tolvaptan OD tablet with water first), formulation and dosing regimen, subjects 
within group, and administration period (Period 1, Period 2, and Period 3) as 
factors.  The analysis will use natural logarithms. 
2) For the AUCt and Cmax of tolvaptan, the 90% confidence intervals (CIs) of the 
ratio of the geometric mean values for the 2 formulations (OD tablet without 
water vs conventional tablet and OD tablet with water vs conventional tablet) will 
be calculated.  Bioequivalence between the formulations and between the dosing 
regimens is to be demonstrated when the 90% confidence intervals fall inside the 
range of ln(0.8) to ln(1.25).  Bioequivalence between the OD tablet and 
conventional tablet is to be established when the bioequivalence criteria are met 
between the OD tablet administered without water and conventional tablet and 
also between the OD tablet administered with water and conventional tablet.  
When an add-on subject study is conducted, bioequivalence is to be assessed in 
the same manner using the pooled data of both the main study and add-on subject 
study. 
3) When there are subjects without evaluable parameters across Periods 1, 2, and 3, 
sensitivity analysis including those subjects will be performed. 
 
7.4.2 
Reference Variable Analyses 
For the AUC∞, MRT∞, tmax, and λz of tolvaptan, data (excluding tmax) will be log-
transformed and analysis of variance (ANOVA) will be performed using group (group 
receiving conventional tablet first, group receiving OD tablet without water first, and 
group receiving tolvaptan OD tablet with water first), formulation and dosing regimen, 
subjects within group, and administration period (Period 1, Period 2, and Period 3) as 
factors.  The analysis will use natural logarithms.  The effects of the formulation and 
dosing regimen will be analyzed at a significance level of 5%. 
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7.5 
Analysis of Demographic and Baseline Characteristics 
The distribution (or descriptive statistics) of the age, height, body weight (at screening), 
BMI, and medical history or current symptoms of the bioequivalence analysis set (per 
group and entire analysis set) will be calculated in each cohort.  If necessary, the same 
calculation will be performed for other analysis sets. 
7.6 
Safety Analysis 
Analysis will be performed by formulation and dosing regimen in each safety analysis set 
per cohort.  Values obtained immediately before IMP administration in each period will 
be handled as baseline. 
7.6.1 
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  The incidence of the following events will be 
summarized: 
 Treatment-emergent AEs (TEAEs) 
 TEAEs by severity 
 TEAEs with an outcome of death 
 Serious TEAEs 
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP. 
7.6.2 
Clinical Laboratory Data 
For each laboratory parameter (excluding qualitative urine tests), descriptive statistics of 
measurements and changes from baseline at each time point will be calculated.  For 
qualitative urine tests, a shift table comparing results to baseline by time point will be 
created.  For each laboratory parameter other than qualitative urine tests, a shift table 
summarizing the test results at each time point classified into “within normal” “below the 
lower limit of normal,” or “above the upper limit of normal” (using the institutional 
reference ranges) with comparison to baseline will be created. 
7.6.3 
Physical Examination and Vital Signs 
For each physical examination parameter, a shift table summarizing the findings at each 
time point compared to baseline will be created. 
For each vital sign parameter, descriptive statistics of measurements and changes from 
baseline at each time point will be calculated. 
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7.6.4 
Electrocardiogram Data 
For each 12-lead ECG parameter, descriptive statistics of measurements and changes 
from baseline at each time point will be calculated.  A shift table of ECG findings at each 
time point compared to baseline assessments will be created.  Categorical analysis of 
corrected QT intervals (QTcF and QTcB) and their changes from baseline at each time 
point will be performed to calculate the number and percentage of subjects. 
7.7 
Decision on Whether to Conduct an Add-on Subject Study 
When bioequivalence is not demonstrated due to insufficient samples in the main study, 
an add-on subject study in additional subjects may be conducted once in accordance with 
the procedures of the main study.  When bioequivalence is demonstrated in only one of 
the cohorts, an add-on subject study will be conducted in the cohort in which 
bioequivalence is not demonstrated. 
The add-on subject study must enroll at least half the number of subjects enrolled in the 
main study.  An add-on subject study will not be conducted when: 
1) When the point estimates of the differences in mean log-transformed AUCt and 
Cmax between the conventional tablet and OD tablet do not fall inside the range of 
ln(0.8) to ln(1.25) in the main study; or 
2) The sample size calculated from the results of the main study for the add-on 
subject study is ethically inappropriate and/or not scientifically feasible. 
 
When data from the add-on subject study are pooled with those of the main study for 
analysis, the study will be included as a variation factor in the analysis. 
8 
Management of Investigational Medicinal Product and 
Reference Product 
Tolvaptan OD tablet 15 mg and tolvaptan OD tablet 30 mg are the test products and 
provided to this study as IMPs.  Tolvaptan conventional tablet 15 mg and tolvaptan 
conventional tablet 30 mg will be used as the reference products. 
For full details on Management of the IMPs and reference products, please refer to the IB 
and Clinical Operation Manual. 
8.1 
Packaging and Labeling 
The IMP and reference products will be provided to the IMP manager by the sponsor or 
designated agent.  The IMP will be supplied as bottles.  Each bottle will be labeled to 
clearly disclose that the contents are for clinical trial use, protocol number, IMP name, 
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quantity, lot number, expiration date, storage condition, and sponsor’s name and address.  
The reference products will be provided in commercial packaging. 
8.2 
Storage 
The IMP and reference product will be stored in a securely locked cabinet or enclosure.  
Access will be limited to the IMP manager.  No IMP manager may provide IMP or 
reference product to any subject not participating in this protocol. 
Both the IMP and reference product will be stored at room temperature.The clinical site 
staff will maintain a temperature log in the IMP storage area recording the temperature at 
least once each working day. 
8.3 
Accountability 
The IMP manager must maintain an inventory record of the IMP and reference product 
received, dispensed, administered, and returned. 
8.4 
Returns and Destruction 
Upon completion or termination of the trial, all unused and/or partially used IMP and 
reference product must be returned to the sponsor. 
All IMP and reference product returned to the sponsor must be accompanied by 
appropriate documentation and be identified by protocol number with trial site number on 
the outermost shipping container.  Returned supplies should be in the original containers.  
The assigned trial monitor will facilitate the return of unused and/or partially used IMP 
and reference product. 
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/reference product or medical device after it is released for distribution.  
Examples include, but are not limited to, communications involving: 
 Failure/malfunction of the IMP or reference product to meet any of its specifications 
 Incorrect or missing labeling 
 Packaging issues (eg, damaged, dirty, crushed, missing product) 
 Blister defects (eg, missing, empty blisters) 
 Bottle defects (eg, under/over-fill, no safety seal) 
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 Vial defects 
 Product defect (eg, odor, chipped, broken, embossing illegible) 
 Loss or theft of product 
 
8.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator or IMP manager must record all PQCs identified through any means 
from the receipt of the IMP and reference product from the sponsor, or sponsor’s 
designee, through and including reconciliation and up to destruction, including subject 
dosing.  The investigator or IMP manager must notify the sponsor by e-mail immediately 
after becoming aware of the PQC according to the procedure outlined below. 
 PQC_156-102-00136@otsuka.jp 
Send the information identified in (Section 8.5.2, Information Required for Reporting 
Purposes) to the above email address. 
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above. 
8.5.2 
 
Information Required for Reporting Purposes 
 Description of compliant 
 Reporter identification (eg, subject, investigator, 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) 
 Dosage form/strength (if known) 
 Pictures (if available) 
 Availability for return 
 
8.5.3 
Return Process 
Indicate during the report of the PQC if the complaint sample is available for return.  If 
complaint sample is available for return, return to the sponsor.  If necessary, the sponsor 
will specify the return procedure. 
8.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
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9 
Records Management 
9.1 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the trial site and made 
available for direct access by authorized persons.  Investigator(s)/institution(s) will 
permit trial-related monitoring, audits, IRB review, and regulatory inspection(s) by 
providing direct access to source data/documents by authorized persons as defined in the 
ICF. 
9.2 
Data Collection 
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain: 
 Documentation of the informed consent process, including any revised consents; 
 Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial; 
 The date of the visit and the corresponding Visit or Day in the trial schedule; 
 General subject status remarks, including any significant medical findings.  The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator’s assessment of relationship to IMP must also be recorded; 
 Any changes in concomitant medications or dosages; 
 A general reference to the procedures completed;  
 The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes. 
 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.  Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by a site staff 
member authorized to make the change.  Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data  right data).  If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
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clinician.  If electronic data systems are being utilized, a full audit trail of changes must 
be maintained. 
Information from the trial progress notes and other source documents will be entered by 
investigative site personnel directly onto electronic CRFs in the sponsor’s electronic data 
capture (EDC) system.  Changes to the data will be captured by an automatic audit trail. 
9.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with Section 8 of the ICH GCP Guideline E6 and as required by applicable local 
regulations.  The trial site will take measures to prevent accidental or premature 
destruction of these documents. 
9.4 
Records Retention at the Trial Site 
The trial site will retain all the trial-related documents and records for the period of time 
indicated below, whichever is longer.  However, if the sponsor requires a longer period of 
archiving, the head of the trial site will consult with the sponsor on the period and 
procedures of record retention. 
 The date 2 years after manufacturing and marketing approval date.  However, if the 
head of the trial site receives notification from the sponsor that development has been 
terminated or that results of the trial will not be submitted with the approval 
application, the date 3 years after receipt of such notification. 
 The date 3 years after termination or completion of the trial. 
 
The trial site must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for sponsor to 
collect such records.  The trial site will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and data generated during 
this trial including any data clarification forms received from the sponsor.  Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
10 
Quality Control and Quality Assurance  
10.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws.  As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
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via telephone, e-mail, and written communications.  In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented. 
10.2 
Auditing 
The sponsor’s Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of CRFs with source documents.  The 
investigator agrees to participate with audits. 
Regulatory authorities may inspect the investigator site during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs. 
11 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science (CIOMS) guidelines, and applicable local 
laws and regulations.  Each trial site will seek approval/favorable opinion by an IRB 
according to regional requirements, and the trial site will provide that documentation to 
the sponsor.  The IRB will evaluate the ethical, scientific, and medical appropriateness of 
the trial.  Further, in preparing and handling CRFs, the investigator, subinvestigator and 
their staff will take measures to ensure adequate care in protecting subject privacy.  To 
this end, a subject number or subject identifier will be used to identify each subject.  
Financial aspects, subject insurance, and the publication policy for the trial will be 
documented in the agreement between the sponsor and the trial site. 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region(s) where the trial 
is conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  All IMPs, subject bodily fluids, and/or other 
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the sponsor. 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Subjects will be identified only by unique subject identifier in CRFs.  If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations. 
13 
Amendment Policy 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB.  Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment.  Any amendment will be written by the 
sponsor.  Each amendment will be submitted to the IRB, as required by local regulations.  
Except for “administrative” or “non-substantial” amendments, investigators will wait for 
IRB approval/favorable opinion of the amended protocol before implementing the 
change(s).  Administrative amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the quality or safety of 
IMP(s) used in the trial.  A protocol change intended to eliminate an apparent immediate 
hazard to subjects should be implemented immediately, followed by IRB notification 
within local applicable timelines.  The sponsor will submit protocol amendments to the 
applicable regulatory agencies within local applicable timelines. 
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification.  In such cases, after 
approval/favorable opinion of the new ICF by the IRB, repeat written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented. 
 
14 
Publication Authorship Requirements 
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
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4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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15 
References 
1 
Guidelines for Bioequivalence Studies of Generic Products, PFSB/ELD Notification 
No. 0229-10 (29 Feb 2012). 
2 
Chapter 6 Prescription Drugs: Case Study. In: Japan Pharmacists Education Center, 
editor. 2000 Guidebook for Approval Application for Pharmaceutical Products. p. 89-
97, p. 128-30. 
3 
International Conference on Harmonization (ICH) [homepage on the Internet]. E6: 
Good Clinical Practice:  Consolidated Guideline [finalized 1996 May, corrected 1996 
Jun 1996; cited 2014 Dec 5]. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6/E6_R1_Guideline.pdf. 
4 
Otsuka Pharmaceutical. OPC-41061 (Tolvaptan) Investigator’s Brochure (Japanese 
Translation), edition 17 (Japan). Otsuka report, issued 25 Aug 2015. 
5 
Diletti. E, Hauschke. D, Steinijans. W.V. Sample size determination for 
bioequivalence assessment by means of confidence intervals. Int J Clin Pharmacol 
Ther Toxicol 1991;29(1),1-8. 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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