Clinical trial NCT02020278
Conditions: Hyponatremia
Keywords: Hyponatremia Euvolemic Hypervolemic Serum sodium Dilutional hyponatremia Electrolyte abnormality Electrolyte imbalance Metabolic disease Water-Electrolyte Imbalance
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2016-04-22; Completion date: 2017-10-23
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this trial was to provide 6 months of safety follow-up for children and adolescents with dilutional (euvolemic or hypervolemic) hyponatremia who had previously participated in a tolvaptan hyponatremia trial and to assess the efficacy of tolvaptan in increasing serum sodium for those participants who received optional continuing tolvaptan treatment of variable duration (up to 6 months).

Detailed description:
Core Safety Follow-up Component

• For all participants: To evaluate the post-treatment safety follow-up of children and adolescent participants with dilutional (euvolemic or hypervolemic) hyponatremia who have previously participated in a tolvaptan hyponatremia trial.

Optional Tolvaptan Treatment Component

• For participants who receive optional tolvaptan treatment: To demonstrate that tolvaptan safely and effectively achieves and maintains increased serum sodium concentrations in children and adolescent participants with dilutional (euvolemic or hypervolemic) hyponatremia when used for both multiple short-term treatments, and/or longer chronic treatments.

Arms: arm 1: Participants enrolled in this trial were eligible to receive open-label tolvaptan if they had a clinical need as determined by the investigator and met the eligibility criteria for optional tolvaptan treatment.

Daily dose levels would have included 3.75 milligrams (mg), 7.5 mg, 15 mg, 30 mg, and 60 mg.
Interventions: intervention 1: Tolvaptan
Intervention descriptions: intervention 1: Tolvaptan 3.75-, 7.5-, 15-, and 30-mg spray-dried tablets. Dosage: Depending on age and weight, Tablet (3.75 mg - 60 mg daily). Frequency: Once daily.

Duration: Participants may be eligible to receive short-term or long-term optional tolvaptan treatment at any time during their participation in the trial, with one or more treatment cycles over a 6-month period.

Protocol documents:
Prot_000.pdf: 
Protocol 156-11-294 
Confidential - Proprietary Information 
Protocol number: 156-11-294
Document title: A Phase 3b, Multicenter, Extension Follow-up Trial 
to Evaluate the Long-term Safety of Children and Adolescent 
Subjects With Euvolemic or Hypervolemic Hyponatremia Who 
Have Previously Participated in a Trial of Titrated Oral SAMSCA 
(Tolvaptan)
Version number: 8.0
Date of the document: 09 November 2015
NCT number:    NCT02020278


Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
SAMSCA, Tolvaptan (OPC-41061)
REVISED CLINICAL PROTOCOL
A Phase 3b, Multicenter, Extension Follow-up Trial to Evaluate the Long-term Safety of 
Children and Adolescent Subjects With Euvolemic or Hypervolemic Hyponatremia Who 
Have Previously Participated in a Trial of Titrated Oral SAMSCA(Tolvaptan)
Protocol No. 156-11-294
IND No. 54,200
NDA No. 22-275
EudraCT No. 2013-002810-11
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3b
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States
Sponsor Representatives:
Medical Director
Phone 
 Fax 
E-mail: 
Clinical Management
Phone: 
Fax: 
E-mail: 
Immediately Reportable Event
INC Research (see Appendix 1)
Issue Date:
31 October 2013
Date of Amendment 1:
5 September 2014
Date of Amendment 2:
26 February 2015
Date of Amendment 3: 
9 November 2015
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Protocol Synopsis
Name of Sponsor:  Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Product:  SAMSCA, Tolvaptan 
(OPC-41061)
Protocol No. 156-11-294
IND No. 54,200
NDA No. 22-275
EudraCT No. 2013-002810-11
Protocol Title:
A Phase 3b, Multicenter, Extension Follow-up Trial to Evaluate 
the Long-term Safety of Children and Adolescent Subjects 
With Euvolemic or Hypervolemic Hyponatremia Who Have 
Previously Participated in a Trial of Titrated Oral SAMSCA
(Tolvaptan)
Clinical Phase/Trial 
Type:
Phase 3b, safety follow-up with optional open-label tolvaptan 
treatment component
Treatment 
Indication:
Dilutional (euvolemic or hypervolemic) hyponatremia
Objectives:
The objective of this trial is to provide 6 months of safety 
follow-up for children and adolescents with dilutional 
(euvolemic or hypervolemic) hyponatremia who have 
previously participated in a tolvaptan hyponatremia trial, and to 
assess the efficacy of tolvaptan in increasing serum sodium for 
those subjects who receive optional continuing tolvaptan 
treatment of variable duration (up to 6 months).
Core Safety Follow-up Component

For all subjects:  To evaluate the post-treatment safety 
follow-up of children and adolescent subjects with 
dilutional (euvolemic or hypervolemic) hyponatremia 
who have previously participated in a tolvaptan 
hyponatremia trial.
Optional Tolvaptan Treatment Component

For subjects who receive optional tolvaptan treatment:  
To demonstrate that tolvaptan safely and effectively 
achieves and maintains increased serum sodium 
concentrations in children and adolescent subjects with 
dilutional (euvolemic or hypervolemic) hyponatremia 
when used for both multiple short-term treatments,
and/or longer chronic treatments.
Trial Design:
Core Safety Follow-up Component
This is a 6-month safety follow-up trial in children and 
adolescents with dilutional (euvolemic or hypervolemic) 
hyponatremia who have previously participated in a tolvaptan 
hyponatremia trial.


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Amendment 3 9 Nov 2015
Enrollment in this trial should follow completion or 
discontinuation of the previous tolvaptan hyponatremia trial. 
The subject must have been off investigational medicinal 
product (IMP) for at least 7 days between trials. A longer lapse 
between completion of the previous tolvaptan hyponatremia 
trial and enrollment into this trial is permitted while enrollment 
is open.
Subjects who consent/assent to participate will be followed 
once a month for 6 months, through telephone calls and/or
clinical trial site visits.  Subjects will attend the clinic for the 
baseline visit and a Month 6/end of trial visit.  The remainder of 
the assessments will be conducted through telephone calls.
Optional Tolvaptan Treatment Component
Subjects enrolled in the core safety follow-up component may 
be eligible for optional tolvaptan treatment.  Tolvaptan 
treatment may be short-term treatment (eg, a few days of 
treatment needed per episode of hyponatremia) or long-term 
treatment (eg, treatment for weeks to months). The need for 
treatment for more than 30 days will be assessed by the 
investigator on a case-by-case basis.
Eligible subjects can be treated with tolvaptan at any time 
during the 6-month core safety follow-up component.
Treatment can be discontinued and reinitiated depending upon 
the individual subject’s need (eg, during chemotherapy 
treatments).  If subjects are off tolvaptan treatment 
for ≥72 hours, reinitiation of treatment (a new treatment cycle) 
will require reassessment of the eligibility criteria and will 
begin in a hospital setting.  Tolvaptan should be titrated with 
regular serum sodium assessments. 
Subject Population:
Approximately 100 male or female subjects will be enrolled in 
this trial.  Eligible subjects will need to have participated in a
previous tolvaptan pediatric trial for dilutional (euvolemic or 
hypervolemic) hyponatremia.
Inclusion/Exclusion 
Criteria:
Key inclusion criteria:

Enrollment in one of the previous tolvaptan pediatric trials 
for hyponatremia.

Willingness to be clinically followed for 6 months.
Exclusion criteria:

There are no exclusion criteria for entry into the core 
safety follow-up component of this trial.


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The optional tolvaptan treatment component has additional 
eligibility criteria. 
Trial Sites:
Subjects may be enrolled at approximately 75 clinical trial sites 
globally.
Investigational 
Medicinal Product, 
Dose, Formulation, 
Mode of 
Administration:
Subjects enrolled in this trial may be eligible to receive 
tolvaptan if they have a clinical need as determined by the 
investigator and meet the eligibility criteria for optional 
tolvaptan treatment.
Tolvaptan will initially be supplied as 3.75-, 7.5-, 15-, and 
30-mg spray-dried tablets.  Upon the availability of an age 
appropriate formulation, for children who cannot swallow
tablets, the protocol will be amended to reflect additional 
dosing options.
Tolvaptan tablets will be administered orally once daily (QD), 
preferably in the morning hours, with a dose-proportional 
amount of water.  Doses of 15 mg tolvaptan will be given 
with 240 mL of water, 7.5 mg of tolvaptan will be given with 
120 mL of water, and 3.75 mg of tolvaptan will be given with 
60 mL of water.  Any initiation or titration of tolvaptan must 
occur in a hospital setting.
If a subject is not expected to receive a higher dose of 
tolvaptan, ie, if a stable dose is determined, continued 
administration can be done outside of the hospital setting.  
Subjects can be treated with optional tolvaptan at any time 
while participating in the 6-month core safety follow-up 
component.
Trial Assessments:

Vital signs

Physical examinations

Body height, weight, and growth percentiles

Tanner Staging

Clinical laboratory tests: Serum sodium assessments 
and liver function tests (alanine transaminase [ALT], 
aspartate aminotransferase [AST], total bilirubin [BT])
and creatinine (for subjects on tolvaptan)

Adverse event (AE) reporting

Continued need for tolvaptan treatment after the first 30 
days of treatment

Quality of Life (QoL) assessments
Pharmacokinetics for optional tolvaptan treatment component:

Sparse blood samples for tolvaptan and plasma 


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Amendment 3 9 Nov 2015
metabolite concentrations from subjects dosed with 
tolvaptan for 8 consecutive weeks (one assessment per 
initiation or reinitiation of therapy at 8 weeks).
Criteria for 
Evaluation:
Primary Endpoint:

Change from baseline in serum sodium while tolvaptan 
is being administered
Secondary Endpoints:
Efficacy:

Percentage of subjects who require rescue therapy while 
on tolvaptan treatment

Percentage of subjects who have recurrence of 
hyponatremia while on tolvaptan

Percentage of subjects requiring continuation of 
tolvaptan following 30 days of treatment

Change from baseline in QoL assessments (monthly for 
subjects on tolvaptan)
Safety:

Percentage of subjects with overly rapid correction in 
serum sodium (12 mEq/L [mmol/L]) in 24 hours after 
the first dose at introduction or reintroduction of 
tolvaptan

Changes from baseline in ALT, AST, BT, and creatinine
for subjects on tolvaptan

Frequency of AE reports (including cases of 
dehydration)

Changes from baseline in growth percentiles by visit for 
body height and weight

Tanner Staging progression score (at 6 months)
Pharmacokinetics for tolvaptan treatment:

Plasma concentrations of tolvaptan and metabolites in 
subjects who have continued tolvaptan therapy for 
8 consecutive weeks.
Statistical Methods:
Primary and secondary endpoints will be summarized by 
descriptive statistics. 
Trial Duration:
The core safety follow-up component of the trial will continue 
until approximately 100 enrolled subjects have either completed 
or been early terminated from the core safety component.  


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Subjects may be eligible to receive optional tolvaptan treatment 
at any time during their participation in the trial, which will be 
for 6 months.


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Amendment 3 9 Nov 2015
Table of Contents
Protocol Synopsis...........................................................................................2
Table of Contents...........................................................................................7
List of In-text Tables ...................................................................................13
List of In-text Figures..................................................................................14
List of Appendices........................................................................................15
List of Abbreviations and Definitions of Terms .......................................16
1
Introduction ........................................................................................18
1.1
Nonclinical Data................................................................................................20
1.1.1
Juvenile Toxicity Data....................................................................................22
1.2
Clinical Data......................................................................................................23
1.2.1
Pharmacokinetics/Pharmacodynamics ...........................................................23
1.2.2
Clinical Efficacy.............................................................................................25
1.3
Known and Potential Risks and Benefits ..........................................................28
2
Trial Rationale and Objectives..........................................................29
2.1
Trial Rationale...................................................................................................30
2.1.1
Core Safety Follow-up Component................................................................30
2.1.2
Optional Tolvaptan Treatment Component....................................................30
2.2
Dosing Rationale...............................................................................................31
2.3
Trial Objectives.................................................................................................31
3
Trial Design.........................................................................................32
3.1
Type/Design of Trial .........................................................................................32
3.1.1
Core Safety Follow-up Component................................................................34
3.1.2
Optional Tolvaptan Treatment Component....................................................35
3.1.2.1
Treatment Interruption on Day 30 ..............................................................35
3.2
Trial Treatments ................................................................................................36
3.2.1
Optional Tolvaptan Treatment........................................................................36
3.2.1.1
Tablet Formulation......................................................................................36
3.2.1.2
Titration Guidelines for the Optional Tolvaptan Treatment 
Component..................................................................................................37
3.2.2
Rescue Therapy ..............................................................................................40


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3.2.3
Fluid Restriction .............................................................................................41
3.3
Trial Population.................................................................................................41
3.3.1
Core Safety Follow-up Component................................................................41
3.3.2
Optional Tolvaptan Treatment Component....................................................41
3.4
Eligibility Criteria..............................................................................................43
3.4.1
Informed Consent/Assent ...............................................................................43
3.4.2
Inclusion Criteria ............................................................................................44
3.4.3
Exclusion Criteria...........................................................................................44
3.5
Outcome Variables............................................................................................45
3.5.1
Primary Outcome Variable.............................................................................45
3.5.2
Secondary Outcome Variables .......................................................................45
3.5.2.1
Efficacy Variables.......................................................................................45
3.5.2.2
Safety Variables ..........................................................................................45
3.5.2.3
Pharmacokinetic Variable:  Optional Tolvaptan Treatment 
Component..................................................................................................46
3.6
Measures to Minimize/Avoid Bias....................................................................46
3.7
Trial Procedures ................................................................................................46
3.7.1
Core Safety Follow-up Component................................................................46
3.7.2
Optional Tolvaptan Treatment Component....................................................49
3.7.3
Schedule of Assessments................................................................................53
3.7.3.1
Core Safety Follow-up Component ............................................................53
3.7.3.1.1
Baseline ...................................................................................................53
3.7.3.1.2
Months 1, 2, 3, 4, and 5 ...........................................................................54
3.7.3.1.3
Month 6/Early Termination.....................................................................54
3.7.3.2
Optional Tolvaptan Treatment Component ................................................55
3.7.3.2.1
Pretreatment Baseline Visit .....................................................................56
3.7.3.2.2
Titration Phase.........................................................................................57
3.7.3.2.2.1
Day 1....................................................................................................57
3.7.3.2.2.2
Day 2 up to Day 4................................................................................58
3.7.3.2.3
Days 7, 14, and 21 ...................................................................................59
3.7.3.2.4
Day 30 Interruption: 30 (1) Days Post-first Dose .................................59
3.7.3.2.4.1
Day 31..................................................................................................60
3.7.3.2.4.2
Day 32..................................................................................................60


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3.7.3.2.4.3
Day 33..................................................................................................60
3.7.3.2.4.4
Day 34..................................................................................................61
3.7.3.2.5
Treatment Cycle Month 2:  Month 2 Week 2 and Month 2 Week 4 
(2 days)..................................................................................................62
3.7.3.2.6
Maintenance Phase ..................................................................................63
3.7.3.2.6.1
Treatment Cycle Month 3 (and every month thereafter) (2 days).....63
3.7.3.2.7
Follow-up Phase ......................................................................................64
3.7.3.2.7.1
First Follow-up:  24 (4) Hours Post-last Dose..................................64
3.7.3.2.7.2
Second Follow-up:  7 (1) Days Post-last Dose.................................64
3.7.3.2.7.3
Third Follow-up:  14 (2) Days Post-last Dose..................................65
3.7.4
Efficacy Assessments .....................................................................................65
3.7.4.1
Serum Sodium Concentrations....................................................................65
3.7.4.1.1
Serum Sodium Samples for Efficacy ......................................................65
3.7.4.1.2
Supplemental Sodium Samples for Safety ..............................................65
3.7.4.1.3
Unscheduled Assessments.......................................................................66
3.7.4.2
Quality of Life Assessments .......................................................................67
3.7.5
Safety Assessments.........................................................................................67
3.7.5.1
Adverse Events............................................................................................67
3.7.5.2
Clinical Laboratory Tests:  Core Safety Follow-up Component ................68
3.7.5.3
Clinical Laboratory Tests: Optional Tolvaptan Treatment Component .....68
3.7.5.3.1
Monitoring of Liver Transaminases ........................................................68
3.7.5.4
Physical Examination and Vital Sign Assessments ....................................69
3.7.5.5
Neurological Examination ..........................................................................70
3.7.5.6
Tanner Staging ............................................................................................70
3.7.5.7
Hyponatremia History.................................................................................71
3.7.5.8
Clinical Status Assessment .........................................................................71
3.7.5.9
Vital Status..................................................................................................71
3.7.6
Pharmacokinetic Assessments........................................................................71
3.7.6.1
Blood Collection Times ..............................................................................71
3.7.6.2
Sample Handling and Processing................................................................72
3.7.7
End of Trial.....................................................................................................72
3.7.8
Independent Data Monitoring Committee......................................................72
3.8
Stopping Rules, Withdrawal Criteria and Procedures.......................................72


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3.8.1
Entire Trial or Treatment Component(s)........................................................72
3.8.2
Individual Site.................................................................................................72
3.8.3
Individual Subject Discontinuation ................................................................73
3.9
Screen Failures ..................................................................................................74
3.10
Definition of Completed Subjects.....................................................................74
3.11
Definition of Lost to Follow-up ........................................................................74
3.12
Subject Compliance...........................................................................................75
3.13
Protocol Deviations...........................................................................................75
4
Restrictions..........................................................................................75
4.1
Prohibited Medications......................................................................................75
4.2
Other Restrictions..............................................................................................76
5
Reporting of Adverse Events.............................................................76
5.1
Definitions.........................................................................................................76
5.2
Eliciting and Reporting Adverse Events ...........................................................78
5.3
Immediately Reportable Events ........................................................................79
5.3.1
Hyponatremia-related Adverse Events...........................................................79
5.3.1.1
Rapid Correction of Serum Sodium............................................................79
5.3.1.2
Other Hyponatremia-related Adverse Events .............................................80
5.4
Potential Drug-induced Liver Injury.................................................................80
5.4.1
Liver Transaminase Elevations.......................................................................80
5.4.1.1
Criteria for Discontinuation from the Optional Tolvaptan Treatment 
Component of the Trial due to Liver Transaminase Elevations .................82
5.5
Pregnancy..........................................................................................................82
5.6
Procedure for Breaking the Blind......................................................................84
5.7
Follow-up of Adverse Events............................................................................84
5.7.1
Follow-up of Non-serious Adverse Events.....................................................84
5.7.2
Follow-up of Serious Adverse Events ............................................................84
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring After 
Last Scheduled Contact ..................................................................................85
6
Pharmacokinetic/Pharmacodynamic Analysis................................85
6.1
Pharmacokinetic Analysis.................................................................................85
7
Statistical Analysis..............................................................................85
7.1
Sample Size.......................................................................................................85


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7.2
Datasets for Analysis.........................................................................................85
7.3
Handling of Missing Data .................................................................................86
7.4
Primary and Secondary Outcome Analysis.......................................................86
7.4.1
Primary Outcome Analysis.............................................................................86
7.4.2
Secondary Outcome Analyses ........................................................................86
7.4.3
Interim Analysis..............................................................................................87
7.5
Analysis of Demographic and Baseline Characteristics....................................87
7.6
Safety Analyses .................................................................................................87
7.6.1
Adverse Events ...............................................................................................87
7.6.2
Clinical Laboratory Data ................................................................................87
7.6.3
Physical Examination and Vital Signs Data ...................................................87
8
Management of Investigational Medicinal Product........................88
8.1
Packaging and Labeling ....................................................................................88
8.2
Storage...............................................................................................................88
8.3
Accountability ...................................................................................................88
8.4
Returns and Destruction....................................................................................88
8.5
Reporting of Product Quality Complaints.........................................................89
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................89
8.5.2
Information Required for Reporting Purposes ...............................................89
8.5.3
Return Process ................................................................................................90
8.5.4
Assessment/Evaluation...................................................................................90
9
Records Management.........................................................................90
9.1
Source Documents.............................................................................................90
9.2
Data Collection..................................................................................................90
9.3
File Management at the Trial Site.....................................................................91
9.4
Records Retention at the Trial Site....................................................................92
10
Quality Control and Quality Assurance...........................................92
10.1
Monitoring.........................................................................................................92
10.2
Auditing.............................................................................................................93
11
Ethics and Responsibility...................................................................93
12
Confidentiality ....................................................................................93
13
Amendment Policy..............................................................................94


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15
References............................................................................................96


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List of In-text Tables
Table 2.2-1
Starting Tolvaptan Tablet Doses as mg/kg of Body Weight .........31
Table 3.2.1.2-1
Starting Tolvaptan Doses With or Without Potent or 
Moderate CYP3A4 Inhibitors........................................................38
Table 3.4.2-1
Inclusion Criteria for Core Safety Follow-up Component ............44
Table 3.7.1-1
Core Safety Follow-up Component:  Schedule of 
Assessments for All Subjects.........................................................47
Table 3.7.2-1
Schedule of Assessments for Each Treatment Cycle.....................50
Table 3.7.4.1.2-1
Serum Sodium Assessments During the Optional Tolvaptan 
Component
................................................................................66
Table 3.7.5.2-1
Clinical Laboratory Tests During Core Safety Follow-up.............68
Table 3.7.5.3-1
Clinical Laboratory Tests During Optional Tolvaptan 
Treatment
................................................................................68
Table 4.1-1
List of Cytochrome P450 3A4 Inhibitors (Partial List) .................76


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List of In-text Figures
Figure 1.2.2-1
Mean (Standard Error) Changes From Baseline in Serum 
Sodium Concentration Following Tolvaptan or Placebo 
Treatment for 30 Days and at 7 Days Following Withdrawal 
of Therapy (Trials 156-02-235 and 156-02-238 [SALT 1 and 
2] Combined) ................................................................................27
Figure 1.2.2-2
Mean (Standard Error) Serum Sodium Concentration Over 
Time From the Parent Trials (156-02-235 and 156-03-238 
[SALT 1 and 2]) to the Open-label Extension Trial (156-03-
244 [SALTWATER]); All Subjects (Observed Case)...................27
Figure 3.1-1
Trial Design Schematic..................................................................33
Figure 3.2.1.2-1
Titration Scheme............................................................................39


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List of Appendices
Appendix 1
Names of Sponsor Personnel .........................................................98
Appendix 2
Institutions Concerned With the Trial............................................99
Appendix 3
Handling and Shipment of Bioanalytical Samples ......................101
Appendix 4
Tanner Staging.............................................................................102
Appendix 5
Optional Tolvaptan Treatment Component:  Eligibility 
Criteria
..............................................................................103
Appendix 6
Optional Tolvaptan Treatment Component:  Laboratory 
Assessment Schedule...................................................................105
Appendix 7
Protocol Amendments..................................................................106


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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
7DFU
7-day follow-up
ADPKD
Autosomal dominant polycystic kidney disease
AE
Adverse event
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC
Area under the concentration-time curve
AUCt
Area under the concentration-time curve calculated to the last 
observable concentration at time t
AUC
Area under the concentration-time curve during the dosing interval 
at steady state
AVP
Arginine vasopressin
BSL
Baseline
BT
Total bilirubin
BW
Body weight
CHF
Congestive heart failure
CIOMS
Council for International Organizations of Medical Sciences
CL/F
Apparent clearance of drug from plasma after extravascular 
administration
Cmax
Maximum (peak) plasma concentration
CYP
Cytochrome P450
DDAVP
1-deamino-8-D-arginine vasopressin
DILI
Drug-induced liver injury
eCRF
Electronic case report form
ED3
Dose required to triple the urine output
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
ET
Early termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IDMC
Independent data monitoring committee
IEC
Independent ethics committee
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional review board
IRE
Immediately reportable event
IV
Intravenous
Ki
Inhibition constant


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LFT
Liver function test
MHRA
Medicines and Healthcare Products Regulatory
NA
Not applicable
OAPI-EQC
Otsuka America Pharmaceutical, Inc.-Ethics, Quality and
Compliance
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc.
PD
Pharmacodynamic(s)
PIP
Pediatric Investigational Plan
PK
Pharmacokinetic(s)
PO
By mouth
POC
Point of care
PQC
Product quality complaint
QD
Once daily
QoL
Quality of Life
SAE
Serious adverse event
SALT
Study of Ascending Levels of Tolvaptan in Hyponatremia
SALTWATER
Safety and sodium Assessment of Long-term Tolvaptan With 
hyponatremia: A year-long, open-label Trial to gain Experience 
under Real-world conditions
SIADH
Syndrome of inappropriate secretion of antidiuretic hormone
STAT
Immediately
t1/2,z
Terminal-phase elimination half-life
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US
United States
WOCBP
Women of child-bearing potential


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1
Introduction
Sodium is the major extracellular electrolyte and is a key factor in maintaining 
extracellular osmolality and transmembrane electrical and chemical potentials.  Serum 
sodium concentration is maintained within a narrow range (normally 135 to 145 mEq/L
[mmol/L]) to facilitate optimal cellular hydration and neuromuscular function.  Sodium 
concentration is normally balanced through integrated actions of the cardiovascular, 
renal, endocrine, gastrointestinal (GI), and nervous systems.
Hyponatremia is a disease seen in all age groups, including pediatrics, and across a wide 
range of patients “from asymptomatic to the critically ill.”1  It is characterized by a 
subnormal concentration of sodium in the blood (serum sodium < 135 mEq/L [mmol/L]) 
and is manifested by a range of neurologic symptoms which, left untreated, can lead to 
seizure, obtundation, hypoxia, and death.  Hyponatremia is rarely seen in isolation and 
typically is found in association with disorders, behaviors, or circumstances which 
promote an imbalance of fluid/sodium homeostasis.  Children, in particular those 
hospitalized and receiving parenteral fluids (eg, post-operative maintenance and 
hydration with hypotonic fluid), are at risk for developing hyponatremia.2,3
Both forms of hyponatremia, dilutional and depletional, impair normal neurologic
function and therefore represent a disease state.  Furthermore, there is evidence 
suggesting that, in both children and adults, hyponatremia has more serious consequences 
than previously believed.4  Various clinical and nonclinical experiments and case studies 
have documented the role of sodium in maintaining extracellular osmolality and 
transmembrane electrical and chemical potentials.  Sudden decreases in the concentration 
of extracellular sodium lead to influx of water into cells, often resulting in cerebral 
edema, irreversible neurologic damage, respiratory arrest, brainstem herniation, and death 
if not treated quickly and appropriately.5  When hyponatremia persists, osmotic 
adjustments can occur over hours to days through metabolic elimination of electrolytes 
and then osmotically-active organic compounds from the cells.  While these 
compensatory mechanisms can prevent acute brain herniation, chronic symptoms of 
hyponatremia may arise from electrochemical imbalances in cations that are important 
for nerve conduction and/or imbalances in amino acids and neurotransmitters dependent 
on sodium for transport.  Disturbances in these physiological processes lead to symptoms 
and outcomes which depend on a number of factors, including rapidity of onset, severity 
of hyponatremia, persistence of underlying disease, and clinical context (age, sex, 
baseline neurologic function).  In many cases, morbidity and mortality associated with 


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hyponatremia can be shown to be prevented or reversed with appropriate and timely 
correction of serum sodium concentration.
In the adult population, hyponatremia occurs in 7% to 8% of elderly, ambulatory
patients6 and 15% to 20% of hospitalized patients6,7,8,9 making it the most common 
serum electrolyte abnormality that physicians encounter, and a prevalent problem for 
those hospitalized for a wide variety of critical illnesses.  A similar situation exists for 
children in which approximately 25% of hospitalized children were found to have mild 
hyponatremia (serum sodium < 135 mEq/L [mmol/L]) and approximately 1% were found 
to have moderate hyponatremia (serum sodium < 130 mEq/L [mmol/L]).4  Hyponatremia
is associated with significant additional hospital morbidity and cost.10
Children, especially infants, are particularly vulnerable to sodium and other electrolyte 
imbalances because of their relatively immature renal function, increased insensible 
water loss, and limited ability to communicate thirst.  Hence, hyponatremia is not
uncommon in hospitalized children and pediatric patients presenting at the Emergency 
Department.  Hyponatremia in children is most often caused by gastroenteritis and water 
intoxication, the former leading to hypovolemic volume state and requiring fluid 
administration.  Other underlying diseases that can be accompanied by dilutional 
(euvolemic or hypervolemic) hyponatremia are congenital heart failure, liver diseases, 
adrenal insufficiency, and renal disorders.  The syndrome of inappropriate secretion of 
antidiuretic hormone (SIADH) is often associated with central nervous system or 
pulmonary conditions and also malignancies.11 An excess of arginine vasopressin (AVP) 
excretion with impaired free water excretion can lead to hyponatremia in febrile children 
and approximately 30% of these hospitalized children have SIADH.12  In addition, 
several drugs such as thiazide diuretics, antidepressants, anticonvulsants, and 
chemotherapeutics have been associated with SIADH.
The United States (US) Food and Drug Administration (FDA) and the European 
Medicines Agency (EMA) have required that pediatric trials be conducted for tolvaptan 
for the indication of hyponatremia.  This trial is an extension trial to follow children and 
adolescent subjects who participated in a previous tolvaptan pediatric trial for
hyponatremia for safety.  In addition, this trial will allow continued access to tolvaptan to 
those subjects with a clinical need per the investigator’s discretion for 6 months after 
enrollment.


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1.1
Nonclinical Data
Tolvaptan is a vasopressin antagonist that blocks the binding of AVP at the V2 receptors 
of the distal portions of the nephron, thereby inducing water diuresis (aquaresis) without 
depletion of electrolytes.  In vitro binding studies demonstrated that tolvaptan has affinity 
for the human vasopressin V2 and V1a receptors but not V1b receptors.  The receptor 
selectivity potential of tolvaptan for human V2 receptors (inhibition constant 
[Ki] = 0.43 nmol/L) is approximately 30 times that for human V1a receptors 
(Ki = 12.3 nmol/L) and at concentrations not achieved clinically.  Several tolvaptan 
metabolites (DM-4110, DM-4111, and MOP-21826) have affinity for the human V2 or 
V1a receptors but to a lesser degree than tolvaptan.  None of the metabolites appear to 
have affinity for V1b receptors.  Tolvaptan is 1.8 times more potent in binding activity 
than native AVP.
In vivo pharmacology experiments using water loaded, alcohol-anesthetized rats 
indicated that tolvaptan at 3 to 30 g/kg intravenous (IV) dose-dependently antagonized 
the antidiuretic action of exogenous vasopressin.  In conscious mice, rats, and dogs, 
tolvaptan at 0.3, 1, 3, and 10 mg/kg by mouth (PO) caused dose-dependent water diuresis 
(aquaresis), ie, an increase in urine volume and a decrease in urine osmolality.  The dose 
required to triple the urine output (ED3) within 2 hours post dosing in rats was estimated 
to be 0.54 mg/kg and the ED3 after 6 hours in dogs was estimated to be 1.1 mg/kg PO.  In 
the rat model of acute progressive hyponatremia, tolvaptan (0, 1, 3, and 10 mg/kg PO) 
produced a clear dose-dependent aquaresis over the dosing duration, which resulted in a 
gradual increase in plasma sodium concentration and a decrease in the mortality rate.  In 
severe hyponatremia, mortality rate decreased from 47% in 1-deamino-8-D-arginine 
vasopressin (DDAVP) and water loaded rats to 38% in the 1 mg/kg dose group, and no 
deaths were seen in the 3 and 10 mg/kg dose groups of tolvaptan-treated rats.  In the rat 
model of chronic hyponatremia induced by DDAVP infusion (1 ng/hour subcutaneous) 
and liquid diet, plasma sodium concentration was reduced to about 110 mEq/L and 
maintained at that level without any deaths.  Oral dose titration of tolvaptan from 0.25 to 
8 mg/kg gradually increased plasma sodium concentration to the normal levels, and 
improved the wet weight of kidney and water content in the brain and heart, which were 
increased by sustained hyponatremia.13
In a dog model of pacing-induced congestive heart failure (CHF), tolvaptan alone exerted 
aquaretic effects without activation of sympathetic and renin-angiotensin-aldosterone 
systems and produced a significant decrease in cardiac preload without affecting cardiac 
afterload or renal functions.  Tolvaptan did not affect the human ether-a-go-go-related 


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gene channel current at the tested concentration up to 2 10−6 mol/L, which was the 
solubility limit for the external solution.  In conscious dogs, tolvaptan at doses of up to 
1,000 mg/kg PO showed no significant changes in the ST segment, QRS width, QT 
interval, and corrected QT interval when compared to the control group.  In an action 
potential duration study in the guinea pig ventricular papillary muscle, tolvaptan did not 
affect any of the parameters studied (resting membrane potential, action potential 
amplitude, maximum aortic velocity, action potential duration at 30%, 60%, and 90% 
repolarization) at tested concentrations of up to 3 10−5 mol/L, which was about 30-fold 
higher than the maximum serum concentrations in humans at an oral clinical dose of 
60 mg of the spray-dried formulation.
Based on results from single-dose toxicity studies, the approximate lethal dose of 
tolvaptan is higher than 2,000 mg/kg in rats and dogs.  The nontoxic dose of the 
compound is estimated to be 1,000 mg/kg/day in the males, and 100 mg/kg/day in the 
females in a 26-week repeated oral dose study in rats and 100 mg/kg/day in both males 
and females in a 52-week repeated oral dose study in dogs.  The exposures in animals at 
these nontoxic dose levels are 4.0 to 13.1 times higher than that in humans following 
administration of the compound at a dose of 60 mg/day.
No deleterious changes in copulation or fertility were seen in the fertility studies in rats.  
No male-factor effects were exhibited in offspring of treated male rats.  No increases in 
fetal mortality or malformation were seen in embryo-fetal development studies in 
pregnant female rats at up to 1,000 mg/kg and in pregnant female rabbits at up to 
100 mg/kg.  However, an additional embryo-fetal development study in pregnant female 
rabbits showed high fetal mortality and a marginal increase in malformations at 
1,000 mg/kg/day.  A prenatal and postnatal development study in rats showed increased 
perinatal death and body weight suppression during the lactation period and after 
weaning in the offspring at 1,000 mg/kg/day.  Drug exposure in the rabbits based on area 
under the concentration-time curve (AUC) values of 3.882 and 16.924 g·h/mL at doses 
of 100 and 1,000 mg/kg/day, respectively, was approximately 1.2- and 5.2-fold higher 
than the AUC value of 3.2376 g·h/mL seen in man receiving a 60-mg/day dose.  No 
genotoxicity of the compound was observed and no antigenicity was evident in guinea 
pigs.  No increases in mortality and tumor incidence were seen in the 2-year 
carcinogenicity study in male mice at doses up to 60 mg/kg/day, in female mice at doses 
up to 100 mg/kg/day, and in rats at doses up to 1,000 mg/kg/day.
Exposure to metabolites present in humans (including DM-4103, which, while inactive at 
the AVP receptors, has the highest human exposure) was adequate in animal models for 


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estimation of effects on toxicity, reproduction, and carcinogenicity.  No evidence of 
long-term pharmacologic or toxicologic effects was seen.
Toxicology data suggested that tolvaptan may be safe in humans.  No male-factor effects 
were seen; however, appropriate precautions should be implemented for the inclusion of 
women of childbearing potential in clinical trials.  Additional information relating to 
nonclinical studies conducted with tolvaptan can be found in the current version of the 
Investigator’s Brochure (IB).13
1.1.1
Juvenile Toxicity Data
Six-week repeated oral dose toxicity study of tolvaptan was conducted in juvenile 
Sprague-Dawley rats (Crl:CD[SD]), 25 days of age at the start of administration, 
10 animals of each sex for 30 and 100 mg/kg groups, and 15 animals of each sex for the 
control and 1,000 mg/kg groups) at daily dose levels of 0 (1% [w/v] hypromellose 
solution), 30, 100, or 1,000 mg/kg.  The reversibility of any effects was also assessed 
following a 4-week untreated recovery period using 5 animals of each sex in the control 
and 1,000 mg/kg groups.  In addition, serum concentrations of tolvaptan and its 
2 metabolites (DM-4103 and DM-4107) were determined after dosing on the first day 
(Day 1) and last day (Day 42) of administration.  No deaths occurred during the 
administration or recovery period.  No test article-related effects were noted in clinical 
observation, detailed clinical observation, sensory functional examination, or necropsy.  
Based on the above results, the no observed adverse effect level was judged to be 
100 mg/kg/day for both males and females.13
A 1-week dose range-finding study was conducted in rat pups at 4 or 7 days of age and 
results showed tolvaptan to be lethal at 1,000 mg/kg/day and tolerable at 100 mg/kg/day 
and lower.
In another study, male and female rat pups at 4 days of age were orally administered 
tolvaptan for 9 weeks at doses of 10, 30, and 100 mg/kg/day.  Similar to the above study, 
pharmacologically mediated changes were noted in urine volume, water consumption, 
and urine electrolytes at all doses.  Dilated renal pelvis considered to be attributable to 
increased urine volume during very early infancy was noted in males at 30 mg/kg/day 
and higher and females at 100 mg/kg/day.  Toxicities were noted at 100 mg/kg/day, 
including death in one male, suppressed body weight gain and food consumption in males 
and females, and delayed balanopreputial separation and prolonged prothrombin time in 
males. Except for prolonged prothrombin time, all changes noted during the 
administration period showed reversibility after a 4-week recovery period. The no 


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observed adverse effect level in both males and females was judged to be 
30 mg/kg/day.13
1.2
Clinical Data
Tolvaptan was approved by the United States (US) Food and Drug Administration (FDA) 
on 19 May 2009, by the European Medicines Agency (EMA) on 03 Aug 2009, and 
subsequently in 10 other countries for the treatment of specific forms of hyponatremia.  
Tolvaptan was approved by the Japanese Ministry of Health, Labour, and Welfare  on 
27 Oct 2010 for the adjunct treatment of volume overload in heart failure when adequate 
response is not obtained with other diuretics; in September 2013 for body fluid retention 
in hepatic cirrhosis when adequate response is not obtained with other diuretics; and in 
March 2014 for suppression of progression of autosomal dominant polycystic kidney 
disease (ADPKD) with increased kidney volume and a rapid rate of increase.  Phase 3 
development for hepatic edema has been completed in China.  Tolvaptan is also being 
developed for the treatment of ADPKD in the US; for the adjunct treatment of chronic 
renal failure treated with peritoneal dialysis and hematodialysis or hemodiafiltration, for 
carcinomatous edema in Japan, and for cardiac edema in China and Taiwan. Tolvaptan, 
under the brand name Jinarc®, is approved to treat ADPKD in Canada and the European 
Union (EU).  As of 31 Mar 2015, the tolvaptan clinical development program consists of 
105 trials; 97 trials had been completed worldwide, 4 trials were terminated, and 8 trials 
were ongoing. More information is available in the IB.13
1.2.1
Pharmacokinetics/Pharmacodynamics
Since inception of the program, a total of 53 clinical pharmacology trials have been 
completed with tolvaptan (as of 31 Mar 2015) in healthy subjects or special populations 
in Japan, the United Kingdom, China, Korea, Argentina, and the US.
In healthy subjects following IV dosing, the terminal-phase elimination half-life (t 1/2,z) 
of tolvaptan is about 3 hours.  Following single oral tablet doses, the t1/2,z of tolvaptan 
(0.00005 w/v% at 25C) is pH independent.  At lower doses, tolvaptan is mostly 
absorbed from the upper GI tract so the decline of the terminal portion of the 
concentration curve reflects elimination process only.  With increasing dose, there is 
continued absorption of tolvaptan from the GI tract such that the rate of decline of the 
terminal portion of the concentration curve is reflective of both absorption and 
elimination processes.13
The limited early absorption of tolvaptan is exemplified by the fact that the maximum 
(peak) plasma concentration (Cmax) values show less than dose proportional increases 


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from 30 to 240 mg and then a plateau at doses from 240 to 480 mg.  Despite the changes 
in tolvaptan absorption, tolvaptan AUC values increase proportionally with increasing 
dose and apparent clearance of drug from plasma after extravascular administration 
(CL/F) values are unchanged for single doses of 30 to 480 mg.13
Tolvaptan concentrations do not accumulate following once daily dosing.  Following 
300-mg doses, Cmax and AUC during the dosing interval at steady state (AUC) were 
only 4.2- and 6.4-fold higher, respectively, when compared with the 30-mg dose.  This 
indicates bioavailability decreases with increasing dose.  Mean (range) absolute 
bioavailability of tolvaptan when administered as a 30-mg tablet was 56% (42% to 80%).
Trials in subjects with hyponatremia secondary to liver disease showed that following a 
single oral dose, tolvaptan concentrations increase dose proportionally from 5 to 60 mg.  
The clearance following single oral doses of tolvaptan was independent of the dose and 
similar to clearance in healthy subjects.  Following multiple oral doses, tolvaptan 
concentrations accumulated 2-fold and clearance was decreased about 50%.13
Once a day dosage regimen trials in CHF subjects with extracellular volume expansion 
showed that tolvaptan concentrations increased less than proportionally with dose upon 
multiple dosing regimens (10, 15, 30, 60, 90, and 120 mg once daily for 13 days) in this 
subject population.  The t1/2,z and CL/F were unchanged across dose groups.  Compared 
to healthy subjects, the disposition of tolvaptan is slower with longer t1/2,z (7.8 to 
11.1 hours) and smaller CL/F (0.9 to 3.3 mL/min/kg).  The Cmax was 2- to 2.5-fold 
greater than that of healthy subjects (at 60- and 90-mg doses).  The median volume of 
distribution following extravascular administration of tolvaptan ranged from 1 to 2.5 L/kg 
and was not different from healthy subjects.
Tolvaptan is a sensitive substrate for cytochrome P450 (CYP) 3A4 and has no inhibitory 
activity at CYP3A4.  Tolvaptan administration does not produce clinically significant 
changes in amiodarone, warfarin (or its 7-hydroxy and 10-hydroxy metabolites), 
lovastatin, furosemide, or hydrochlorothiazide plasma concentrations.  Steady state 
digoxin concentrations were increased approximately 20% (as determined by AUC).
When administered with the potent CYP3A4 inhibitor ketoconazole, the 
ketoconazole + tolvaptan/tolvaptan alone ratio for tolvaptan mean Cmax and AUC from 
time zero to infinity values were 3.48 and 5.40, respectively.  Therefore, a 4-fold 
reduction in tolvaptan dose is recommended when initiating tolvaptan therapy in subjects 
using potent CYP3A4 inhibitors and a 2-fold reduction in tolvaptan dose is recommended 
for subjects using moderate CYP3A4 inhibitors.  Lovastatin increases tolvaptan Cmax by 


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approximately 20% but CL/F is unchanged.  Tolvaptan Cmax and AUC calculated to the 
last observable concentration at time t (AUCt) are increased 1.9- and 1.6-fold, 
respectively, when tolvaptan is coadministered with grapefruit juice.  Following 
coadministration with 600 mg once daily rifampin at steady state, tolvaptan Cmax and 
AUCt are decreased 83% and 87%, respectively.
When 30- or 60-mg tablet doses were given following a standard high-fat, high-calorie 
meal, no clinically significant differences in urine output were observed.14,15
Following multiple oral doses, the tolvaptan metabolite DM-4103 was found to 
accumulate.  This metabolite has no pharmacological activity and has shown an 
acceptable toxicity profile.  The metabolite has not been shown to accumulate in 
nonclinical toxicokinetic studies; however, in a 26-week study in rats, DM-4103 plasma 
concentrations greater than those expected at the dose used in this trial revealed no 
evidence of time-dependent toxicological effects.13
Tolvaptan increases urine excretion rate at concentrations around 20 ng/mL and maximal 
urine excretion rates are reached between 100 and 150 ng/mL.  A single oral dose trial in 
healthy subjects using doses from 60 to 240 mg showed that there were 1) no further 
increases in urine excretion rate with doses beyond 180 mg; 2) no further increases in 
zero to 24 hour urine excretion with doses beyond 180 mg; and 3) as dose was increased, 
increases in urine excretion were sustained over time.  Tolvaptan elevated electrolyte-free 
water clearance to a positive value, increased serum sodium and plasma osmolality, and 
increased plasma AVP concentrations and renin activity, but no dose-related increases 
were observed for any other parameter.
Details of the currently available pharmacokinetic (PK)/pharmacodynamic (PD) data for 
the compound are available in the IB.13
1.2.2
Clinical Efficacy
Thirteen trials involving either exclusive evaluation of subjects with hyponatremia 
(10 trials in which all subjects have hyponatremia and a long-term extension trial) or 
substantial subpopulations of subjects with hyponatremia (3 CHF trials - not all subjects 
in these trials had hyponatremia,) have been conducted.
Briefly, in clinical trials, tolvaptan has consistently shown to improve or normalize serum 
sodium concentrations in hyponatremic subjects, regardless of etiology.  In clinical trials 
in subjects with volume overload and hyponatremia, the effect of tolvaptan on serum 
sodium is combined with a reduction in fluid overload, as shown by greater decreases in 


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body weight compared to placebo.  Additionally, subjects with liver disease responded to 
higher doses of tolvaptan with reductions in body weight.13
Data from two phase 3, multicenter, randomized, double-blind, placebo-controlled trials 
evaluating tolvaptan in euvolemic and hypervolemic hyponatremia subjects (Study of 
Ascending Levels of Tolvaptan in Hyponatremia [SALT] 1 and 2 trials) served as the 
basis for approval in the US and Europe.  A total of 448 subjects were randomized in 
these trials (oral placebo n = 223 and tolvaptan n = 225) for a 30-day treatment period.  
The first single daily dose (15 mg) was monitored in-hospital with optional fluid 
restriction.  Patients were discharged and fluid intake and tolvaptan (30 or 60 mg) were 
titrated as clinically indicated.
The primary efficacy endpoints for the SALT 1 and 2 trials were the average daily AUC 
of change from baseline in serum sodium concentration up to Day 4 and up to Day 30.  
For both primary endpoints, the difference between the treatment groups were highly 
statistically significant (p < 0.0001), and demonstrated that serum sodium concentrations 
increased more with tolvaptan than placebo over the first 4 days and the entire 30 days.  
Significance was seen in both mild and severe hyponatremia subgroups (p < 0.001).  
When tolvaptan therapy was stopped, serum sodium concentrations fell to the level of 
placebo concentrations (Figure 1.2.2-1) but recovered upon resumption of tolvaptan 
therapy (Figure 1.2.2-2).


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Treatment Day
8h 2
3
4
11
18
25
30
Serum  Sodium  (m Eq/L)
124
126
128
130
132
134
136
138
140
Tolvaptan 15-60mg
Placebo
Base-
line
7DFU
Day 1
p<0.0001
7DFU = 7-day follow-up.
Figure 1.2.2-1
Mean (Standard Error) Changes From Baseline in Serum 
Sodium Concentration Following Tolvaptan or Placebo 
Treatment for 30 Days and at 7 Days Following Withdrawal of
Therapy (Trials 156-02-235 and 156-03-238 [SALT 1 and 2] 
Combined)
156-02-235 (SALT 1) /156-03-238 (SALT 2)
BSL
8h
2
3
4
7
14
21
30
7FU
Serum Sodium Concentration (mEq/L)
125
130
135
140
Placebo 
156-03-244 (SALTWATER)
BSL
1
14
31
10
18
26
34
42
50
58
70
82
94
Tolvaptan 15-60mg (prior Placebo)
Tolvaptan 15-60 mg
FU
Day
Week
Washout
Early 
Term
Day
Day 1
BSL = Baseline, 7FU = 7-day follow-up, FU = follow-up.
SALTWATER = Safety and sodium Assessment of Long-term Tolvaptan With hyponatremia:  A year-
long, open-label Trial to gain Experience under Real-world conditions
Figure 1.2.2-2
Mean (Standard Error) Serum Sodium Concentration Over 
Time From the Parent Trials (156-02-235 and 156-03-238 
[SALT 1 and 2]) to the Open-label Extension Trial (156-03-244 
[SALTWATER]); All Subjects (Observed Case)


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Details of the currently available efficacy data for tolvaptan are available in the IB.13
1.3
Known and Potential Risks and Benefits
As of 31 Mar 2015, pooled exposure data are available from 93 trials, including 
7373 subjects worldwide who were exposed to oral doses of tolvaptan spray-dried tablets.  
The extent of exposure to oral tolvaptan by dose in the pooled database (N = 7373) 
comprises 3115 subjects in trials for heart failure, 511 subjects in trials for hyponatremia, 
961 subjects in the pivotal long-term ADPKD trial, 270 subjects in short-term trials for 
ADPKD or renal impairment, 437 subjects in trials for cardiac edema, 855 subjects in 
trials for hepatic edema, 43 subjects in trials for chronic renal failure, 43 subjects in a trial 
for carcinomatous edema, 37 subjects with renal impairment in a phase 1 trial, and 
1101 healthy subjects in clinical pharmacology trials.
The most commonly reported treatment-emergent adverse events (TEAEs) (by > 10% 
incidence and greater than placebo) in healthy subjects treated with tolvaptan were thirst, 
pollakiuria, and headache.  Headache was the most commonly reported TEAE in the 
placebo subjects.
The hyponatremia program comprised 835 subjects from 12 short-term trials involving 
either exclusive evaluation of subjects with hyponatremia (9 trials) or substantial 
subpopulations of subjects with hyponatremia (3 CHF trials). The 511 subjects in the 
hyponatremia trials were exposed to oral tolvaptan doses ranging from 5 to 60 mg, for a 
total of 8339 days of exposure. In the 9 hyponatremia trials, the most commonly reported 
TEAEs (> 5% incidence) in the tolvaptan subjects were thirst, dry mouth, peripheral 
oedema, nausea, dizziness, fatigue, constipation, headache, ascites, diarrhoea, pollakiuria, 
asthenia, hypotension, pyrexia, and hypokalaemia.  The most commonly reported TEAEs 
(> 5% incidence) in the placebo subjects were peripheral oedema, diarrhoea, headache, 
ascites, vomiting, dyspnoea, nausea, and hypotension.  The IB provides a review of the 
adverse events (AEs) experienced with tolvaptan during clinical trials.13
Analyses of the completed 3-year pivotal Trial 156-04-251 (double-blind, 
placebo-controlled trial to determine long-term safety and efficacy of oral tolvaptan in 
adult subjects with ADPKD) have revealed new and important safety information.  In this 
trial, a new signal for imbalanced elevations of liver transaminases in subjects with 
ADPKD receiving tolvaptan compared with placebo was detected and formally 
adjudicated by an expert panel blinded to treatment.
Based on the analyses of combined central and local laboratory data, a total of 3 tolvaptan 
subjects in the ADPKD program (2 in Trial 156-04-251 and 1 in the ongoing extension 
Trial 156-08-271) were identified as meeting Hy’s Law laboratory criteria (ie, alanine 


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transaminase [ALT] or aspartate transaminase [AST] > 3 times the upper limit of normal 
[ULN] accompanied by total bilirubin [BT] > 2 ULN with the elevated BT occurring 
within 30 days after the transaminase elevation).  Based on review of the data from the 
adjudicated subjects, the transaminase elevations associated with tolvaptan treatment 
were reversible (ie, returned to 3 ULN typically within 1 to 4 months), and were not 
associated with fulminant liver failure, or permanent liver injury or dysfunction.
No association with tolvaptan dose or exposure was found.  The results do not appear to 
suggest an association between tolvaptan and age or sex with respect to an increased risk 
of potential liver injury.
Retrospective evaluation of data from the hyponatremia and heart failure clinical 
development programs did not reveal an imbalance of subjects with elevated ALT 
between tolvaptan and placebo groups.  In addition, no signal of tolvaptan-induced 
hepatotoxicity has been detected in the review of the postmarketing experience to date for 
any non-ADPKD indication.  However, these data are not adequate to exclude the 
possibility that patients treated with tolvaptan are at a potential increased risk for liver 
injury.  Further details regarding this issue can be found in the IB.13
In clinical trials, tolvaptan consistently has shown a beneficial effect in hyponatremic 
subjects by improving serum sodium concentrations, in many cases to normalization.  In 
subjects with heart failure, tolvaptan has consistently shown a beneficial effect by 
improving fluid balance through the induction of increased urine volume.  In subjects 
with volume overload and hyponatremia receiving optimal standard heart failure therapy, 
the effect of tolvaptan on serum sodium is combined with a reduction in fluid overload, 
as shown by greater decreases in body weight as compared with placebo.  In subjects 
hospitalized with worsening heart failure and symptoms of fluid overload, tolvaptan 
treatment, in addition to continued conventional therapy including diuretics, increased 
weight reduction, improved subject-assessed dyspnea and pedal edema, normalized 
serum sodium concentrations in subjects with hyponatremia, and maintained renal 
function in comparison to placebo.
Additional safety information can be found in the IB.13 To date, no clinical trials in 
children have been completed with tolvaptan.
2
Trial Rationale and Objectives
It is recognized that the pediatric population is a vulnerable subgroup and there are risks 
in conducting a clinical trial in the pediatric population.  However, given the possible 


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serious and life-threatening consequences of untreated hyponatremia, it is necessary to 
study hyponatremia treatment in children.  Children have different physiology and 
metabolisms from adults and, therefore, it is not sufficient to study hyponatremia 
treatment in the adult population to determine the proper course of treatment for 
hyponatremia in the pediatric population.  A clear understanding of exposure-response in 
adults that can be applied to pediatrics (or from one pediatric group to another) has not 
yet been established, furthering the need for this trial.16
Every effort will be made to anticipate and reduce known risks.  This trial was designed 
to minimize the number of participants and minimize the number of procedures, 
consistent with good study design.17  Children will be monitored for signs of distress 
during this trial.  The risk threshold for subjects will be monitored by the investigator.  A 
detailed list and description of the safety monitoring to be conducted during this trial can 
be found in Section 3.7.5.
This trial will consist of a core safety follow-up component and an optional tolvaptan
treatment component. The rationale and objectives of the 2 components of the trial are 
described in Section 2.1.1 (core safety follow-up component) and Section 2.1.2 (optional 
tolvaptan treatment component).
2.1
Trial Rationale
2.1.1
Core Safety Follow-up Component
The primary purpose of this component of the trial is to follow children and adolescent 
subjects who have previously participated in a tolvaptan trial for dilutional (euvolemic or 
hypervolemic) hyponatremia, for safety. The duration of safety follow-up will be 
6 months.
Subjects in the core safety follow-up component may either receive no treatment, be 
treated per the local standard of care for hyponatremia, or if eligible, receive treatment 
with tolvaptan.  
2.1.2
Optional Tolvaptan Treatment Component
While participating in the core safety follow-up component, an enrolled subject may be 
eligible to receive optional tolvaptan treatment at any time during the 6-month period. 
The primary purpose of this component of the trial is to follow children and adolescent 
subjects who receive optional tolvaptan treatment for dilutional (euvolemic or 
hypervolemic) hyponatremia, for safety and for efficacy.


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Based on the various underlying etiologies contributing to hyponatremia, the need for 
treatment may differ for each individual subject. This trial is designed to accommodate 
short-term, long-term, and repeated tolvaptan treatment cycles as necessary within the 
6-month core safety component period.
Each tolvaptan treatment cycle will consist of a titration phase and a maintenance phase.
Each treatment cycle will have a planned interruption after 30 days of treatment to assess
the need for continued treatment. Exceptions to this planned interruption are described in 
Section 3.1.2.1.  Dosing and titration guidelines are detailed in Section 3.2.1.
2.2
Dosing Rationale
In the optional tolvaptan treatment component of the trial, eligible subjects will receive
tolvaptan based on age, weight, and the use of CYP3A4 inhibitors.  
The doses of tolvaptan used in this trial were selected to be comparable to the doses used 
in the pivotal phase 3 trials of tolvaptan for hyponatremia in adults (SALT pivotal trials 
156-02-235 and 156-03-238).18,19
In the pivotal hyponatremia trials,13,18,19 the starting 15-mg dose was administered to 
adult subjects weighing 34.0 to 164.7 kg; in terms of mg/kg, the starting dose of tolvaptan 
ranged from 0.09 to 0.44 mg/kg.  The weight cutoffs for this trial were selected to 
produce mg/kg doses of tolvaptan within the range observed for the adult trials.  Table 
2.2-1 outlines the mg/kg dose ranges for tolvaptan tablet doses and body weights of 10, 
20, 50, 70 (standard adult man), and 100 kg.
It is estimated that subjects 6 years of age weigh approximately 25 kg.20
Table 2.2-1
Starting Tolvaptan Tablet Doses as mg/kg of Body Weight
Tolvaptan 
Tablets
Tolvaptan Doses as mg/kg
BW of 10 kg
BW of 20 kg
BW of 50 kg
BW of 70 kg
BW of 100 kg
3.75 mg
0.375
0.19
-
-
-
7.5 mg
-
0.375
0.15
-
-
15 mg
-
-
0.30
0.21
0.15
BW = body weight
Additional dosing and titration guidelines can be found in Section 3.2.1.
2.3
Trial Objectives
The objective of this trial is to provide 6 months of safety follow-up for children and 
adolescents with dilutional (euvolemic or hypervolemic) hyponatremia who have 
previously participated in a tolvaptan hyponatremia trial, and to assess the efficacy of 


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tolvaptan in increasing serum sodium for those subjects who receive optional continuing 
tolvaptan treatment of variable duration (up to 6 months).
Core Safety Follow-up Component

For all subjects:  To evaluate the post-treatment safety follow-up of 
children and adolescent subjects with dilutional (euvolemic or 
hypervolemic) hyponatremia who have previously participated in a 
tolvaptan hyponatremia trial.
Optional Tolvaptan Treatment Component

For subjects who receive optional tolvaptan treatment: To demonstrate 
that tolvaptan safely and effectively achieves and maintains increased 
serum sodium concentrations in children and adolescent subjects with 
dilutional (euvolemic or hypervolemic) hyponatremia when used for both 
multiple short-term treatments, and/or longer chronic treatments.
3
Trial Design
3.1
Type/Design of Trial
This trial consists of 2 components, a 6-month safety follow-up trial, and an embedded 
optional tolvaptan treatment trial for eligible subjects.  The 2 components are described 
below and illustrated in Figure 3.1-1.


Figure 3.1-1
Trial Design Schematic


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3.1.1
Core Safety Follow-up Component
The core safety follow-up component of the trial is a 6-month period in which pediatric 
subjects (children and adolescents) with dilutional (euvolemic or hypervolemic) 
hyponatremia who previously participated in a tolvaptan hyponatremia trial will be 
followed (at a clinical trial site and/or through telephone calls), regardless of the need for 
treatment for hyponatremia, to assess the long-term safety of tolvaptan. There is no 
screening phase.  
Enrollment into this trial should follow completion or discontinuation from the previous 
tolvaptan hyponatremia trial; the subject must have been off investigational medicinal 
product (IMP) for at least 7 days between trials.  A longer lapse between completion of 
the previous tolvaptan hyponatremia trial and enrollment into this trial is permitted while 
enrollment is open.
The final laboratory assessments for liver function tests (LFTs) from the previous 
tolvaptan trial can serve as the baseline laboratory assessments for this trial if the values 
are within the normal range, and collected within 30 days of the baseline visit for this 
trial.  However, LFTs for these subjects will be collected at Month 1 or Month 2 at a 
clinical site visit or local laboratory.  If LFTs from the previous tolvaptan trial are 
abnormal, or collected > 30 days of the baseline visit of this trial, they will be assessed at 
baseline.  
The last assessments in the previous tolvaptan trial will serve as the baseline assessments 
if collected within 30 days of enrollment into this trial.  Otherwise, assessments will be 
repeated if > 30 days have lapsed since the previous tolvaptan trial. 
Subjects enrolled in this trial will be assessed up to 7 times over the 6 month core safety 
follow-up component of the trial.  The baseline and the Month 6/Early Termination (ET)
visits are performed in the clinic, while assessments during Months 1, 2, 3, 4 and 5 will
be conducted by telephone, unless LFTs are required at Month 1 or Month 2.  During the 
in-clinic visits, subjects are evaluated for relevant trial information.  
Baseline Visit
All subjects will attend the clinic for the baseline visit.
Months 1, 2, 3, 4 and 5
All subjects will receive telephone assessments for Months 1, 2, 3, 4, and 5.  If LFTs are 
required at Month 1 or Month 2, the subject may obtain these results through a clinic visit 
or from a local laboratory. 


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Month 6/End of Trial Visit
All subjects will attend the clinic for the Month 6/End of Trial visit.
3.1.2
Optional Tolvaptan Treatment Component
Subjects enrolled in the 6-month core safety follow-up component may be eligible to 
receive optional tolvaptan treatment for their hyponatremia. Eligibility criteria for 
optional tolvaptan treatment are outlined in Appendix 5.  Eligibility for optional tolvaptan 
treatment must be determined at the pre-treatment baseline visit (Day −4 to Day -1) of 
each dosing cycle.  Eligible subjects can be treated at any time with optional tolvaptan 
during the 6-month core safety follow-up component. Optional tolvaptan treatment 
duration will be case-specific; it can be short-term or long-term, and consist of 1 or more 
treatment cycles.  When a cycle with optional tolvaptan treatment is completed, including 
the Follow-up Phase visits, subjects will continue in the core safety component to 
complete the remainder of visits until Month 6.  Within this trial, tolvaptan treatment will 
not extend beyond the 6-month core safety trial period. If the subject completes the 
6-month core safety component while on optional tolvaptan treatment, the subject will 
complete the Month 6 core safety component visit, terminate treatment, and immediately 
enter the Follow-up Phase. 
If a subject simultaneously participates in both core safety and optional tolvaptan 
treatment components, the visit days will be calculated between both components to 
ensure the assessments can be overlapped, where applicable.
3.1.2.1
Treatment Interruption on Day 30
Thirty days after the start of optional tolvaptan treatment, subjects will interrupt treatment 
for up to 2 doses (Days 31-32).  The need for continuing treatment after this tolvaptan
interruption will be assessed at minimum once daily (or more as needed) during this time.
Subjects who are expected to receive tolvaptan for greater than 30 days duration should 
demonstrate the need for continued treatment by discontinuing tolvaptan for up to 2 
consecutive doses while undergoing close monitoring of serum sodium levels.
However, there is a subgroup of subjects who have an identifiable cause for
hyponatremia that has not (or cannot be) changed that will have an option to be excused 
from this brief interruption of tolvaptan.  Examples of such causes include concomitant 
treatment for refractory seizures with a hyponatremia-inducing medication such as 
oxcarbazepine (which can increase vasopressin production by the pituitary) that cannot 
be changed or discontinued, or subjects with a known underlying hyponatremia inducing 
condition such as volume overload from a failing Fontan repair.


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During this treatment interruption, subjects will have serum sodium levels monitored 
closely. Subjects who demonstrate a decline in serum sodium level will be restarted at 
the prior dose of tolvaptan as per clinician judgment. Subjects whose serum sodium 
declines ≥ 4 mEq/L (mmol/L) or who exhibit symptoms of hyponatremia will be 
immediately placed under direct observation as per clinician judgment and will be 
restarted at their previous dose of tolvaptan unless there is a compelling reason to reduce 
the dose.  Subjects will be closely monitored until stable.
Investigators should consider the overall clinical status of the subject (including 
underlying etiology of hyponatremia and volume assessment), prior response to 
tolvaptan, concomitant medications, age, and weight when determining the appropriate 
dose at which to restart a subject after a brief discontinuation of tolvaptan to assess the 
need for further treatment.  Investigators should discuss any concerns with the medical 
monitor.  

Subjects who resume dosing within 72 hours post last dose (either on Day 
32 or by the morning of Day 33), can do so at the same dose or a lower 
dose without having to go through the full titration cycle again. 

Subjects who have a dosing interruption of ≥72 hours must enter a new
treatment cycle and repeat the full titration cycle in a hospital setting.

Subjects who do not need to continue treatment with tolvaptan will 
proceed directly to the Follow-up Phase (Day 7 Follow-up).  Subjects will 
then continue in the core safety follow-up component and complete 
remaining required visits, as applicable.
The optional tolvaptan treatment component of the trial will be available for the 6-month 
duration of the core safety component for each subject. 
3.2
Trial Treatments
The core safety follow-up component of the trial does not contain any trial specific 
treatments. However, eligible subjects have the opportunity to receive tolvaptan 
treatment in the optional tolvaptan treatment component.
3.2.1
Optional Tolvaptan Treatment
3.2.1.1
Tablet Formulation
Tolvaptan tablets will be administered orally once daily (QD), preferably in the morning 
hours, with a dose- proportional amount of water.  Doses of 15 mg of tolvaptan will be 
given with 240 mL of water, 7.5 mg of tolvaptan will be given with 120 mL of water, and 
3.75 mg of tolvaptan will be given with 60 mL of water. The quantity of water ingested 
with each dose should be recorded. 


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3.2.1.2
Titration Guidelines for the Optional Tolvaptan Treatment 
Component
In the optional tolvaptan treatment component of the trial, eligible subjects will receive 
tolvaptan based on age, weight, and the use of CYP3A4 inhibitors.  Tolvaptan tablets will 
be administered orally QD, preferably in the morning hours.
Tolvaptan doses can be titrated QD and will be based on serum sodium levels assessed at 
24 (± 4) hours following initiation of therapy and each subsequent dose.  Titration 
guidelines are detailed in Figure 3.2.1.2-1.  Titration must occur in a hospital setting.  
Titration may not occur within 24 (± 4) hours of the previous dose and must be based on 
serum sodium assessment obtained > 20 hours post previous dose.  Titration is limited to 
no more than twice the previous dose, and will be limited to the maximum dose per body 
weight.
An age-appropriate formulation is not available for this trial.  Therefore, the following 
subjects will be excluded from the optional treatment component of this protocol:

Subjects < 4 years of age, or weighing < 10 kg, 

Subjects with an inability to swallow tablets, and

Subjects weighing < 20 kg and taking a moderate or potent CYP3A4 
inhibitor 
Table 3.2.1.2-1 outlines starting tolvaptan doses and adjustments when tolvaptan is 
administered concurrently with potent or moderate CYP3A inhibitors.  Tolvaptan doses 
will be reduced 75% and 50% if a potent or moderate inhibitor, respectively, is being 
concurrently administered.  


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Table 3.2.1.2-1
Starting Tolvaptan Doses With or Without Potent or Moderate 
CYP3A4 Inhibitors
Age/Weight
Can 
subject 
swallow a 
tablet?
Starting Dose:  
No CYP 
Inhibitor
Starting Dose:  
Moderate CYP 
Inhibitor
Starting Dose:  
Potent CYP 
Inhibitor
≥4 y AND > 10 to < 20 kg
Yes
3.75 mg
Not eligible for 
treatment
Not eligible for 
treatment
≥4 y AND > 20 to ≤50 kg 
Yes
7.5 mg
3.75 mg
Not eligible for 
treatment
≥4 y  AND > 50 kg
Yes
15 mg
7.5 mg
3.75 mg
Based on the weight versus dose information provided in Table 2.2-1 and taking into 
consideration the concomitant use of a CYP3A4 inhibitor, the starting doses are as 
follows:
Subjects ≥ 4 years of age and weighing ≥ 10 to < 20 kg:

Not taking a moderate or potent CYP3A4 inhibitor will receive a QD oral 
tolvaptan tablet dose of 3.75 mg, with possible up-titration to 7.5 mg and 
15 mg

Taking a moderate or potent CYP3A4 inhibitor are not eligible for 
optional tolvaptan treatment
Subjects weighing ≥20 to ≤50 kg:

Not taking a moderate or potent CYP3A4 inhibitor will receive a QD oral 
tolvaptan tablet dose of 7.5 mg, with possible up-titration to 15 mg and 
30 mg

Taking a moderate CYP3A4 inhibitor will receive half the starting 
tolvaptan tablet dose, eg, 3.75 mg tablet, with possible up-titration to 
7.5 mg and 15 mg.

Subjects are not eligible to receive optional tolvaptan treatment if they are 
taking a potent CYP3A4 inhibitor.
Subjects weighing > 50 kg

Not taking a moderate or potent CYP3A4 inhibitor will recieve a QD oral 
tolvaptan tablet dose of 15 mg, with possible up-titration to 30 mg and 
60 mg

Taking a moderate CYP3A4 inhibitor will receive half the starting 
tolvaptan tablet dose, ie, 7.5 mg, with possible up-titration to 15 mg and 
30 mg


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
Taking a potent CYP3A4 inhibitor will receive one quarter the starting 
tolvaptan tablet dose, eg, 3.75 mg, with possible up-titration to 7.5 mg and 
15 mg.
Subjects not eligible for the optional tolvaptan treatment component still remain eligible 
for the core safety follow-up component.
Subjects eligible for the optional tolvaptan treatment component will titrate according to 
the guidelines listed in Figure 3.2.1.2-1, targeting a final serum sodium concentration 
between 135 and 140 mEq/L (mmol/L).  The clinician-directed target range is also 
acceptable.
Treatment can be discontinued at any time and cycles may be repeated as needed.  If 
subjects are off tolvaptan treatment for ≥72 hours, re-initiation of tolvaptan treatment, 
starting with the pre-treatment baseline visit will occur.  This will require a reassessment 
of the eligibility criteria, a tolvaptan titration period, and will begin in a hospital setting as 
part of a new treatment cycle.
The titration scheme is shown in Figure 3.2.1.2-1.
Figure 3.2.1.2-1
Titration Scheme


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Titration guidelines are designed to ideally achieve a change in serum sodium 
concentration of at least 4 to 8 mEq/L (mmol/L) /24 hours but not ≥12 mEq/L 
(mmol/L)/24 hours.
Tolvaptan dose titration (after the initial dose) must be based on changes in serum sodium 
levels as follows:

If the serum sodium level increases by ≤ 4 mEq/L (mmol/L)/24 hours and the 
subject is still below the therapeutic target for serum sodium level 
(135 mEq/L [mmol/L]), then the tolvaptan dose may be titrated up to the next 
scheduled dose.

If the serum sodium level increases > 4 to ≤8 mEq/L (mmol/L)/24 hours in 
response to tolvaptan treatment and the serum sodium is ≤ 140 mEq/L (mmol/L), 
then the dose of tolvaptan should remain the same for the subsequent day.

If the serum sodium level increases > 8 mEq/L (mmol/L)/24 hours or reaches a 
concentration of > 140 mEq/L (mmol/L), then the next dose of tolvaptan should 
not be given and the medical monitor should be contacted to consider options 
(ie, down-titration, tolvaptan discontinuation, concomitant medication adjustment, 
fluid supplementation and/or withdrawal).

If serum sodium level increases by ≥ 12 mEq/L (mmol/L) in the 24 hour period 
following dosing, or, at any time after dosing, the serum sodium level is 
> 145 mEq/L (mmol/L), the next dose of tolvaptan should not be given and the 
medical monitor should be contacted immediately to consider options.
3.2.2
Rescue Therapy
Rescue therapy is defined as any treatment, eg, hypertonic saline, isotonic saline (with or 
without diuretic for the purpose of increasing the serum sodium level), 
plasmapheresis/dialysis, demeclocycline, urea, lithium, or commercial vaptans intended 
to raise the level of serum sodium during the trial.  Subjects who develop worsening 
hyponatremia symptoms may receive rescue therapy at any time during the trial.  
However, subjects who require rescue therapy during the optional treatment component 
will be discontinued from tolvaptan prior to receiving rescue therapy.
Subjects will continue to be followed per the schedule of assessments in the optional 
tolvaptan treatment component (Follow-up Phase visits).  Treatment with tolvaptan may 
be reinitiated only per consultation with the medical monitor. Subjects who have 
received rescue therapy because of inadequate response to tolvaptan will not be allowed 
to reinitiate tolvaptan treatment.
For subjects participating in the optional tolvaptan component only, serum sodium values 
drawn up to, but not after, the initiation of rescue therapy will be included in the 


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calculation of the efficacy endpoint. Additional guidelines for rescue therapy concerning 
hyponatremia symptoms and decreasing serum sodium level are as follows: 

If a subject has worsening symptoms and/or has a serum sodium level at or below
the baseline value for the current treatment cycle, repeat serum sodium
immediately (STAT) to confirm level, and begin rescue therapy.

If a subject is asymptomatic and serum sodium has decreased by ≥ 4 mEq/L
(mmol/L), but is still above the baseline value, consider need for rescue therapy
according to local standard of care. 

If a subject is asymptomatic and serum sodium has decreased by ≤ 3 mEq/L
(mmol/L) but is still above the baseline value, no action is required.
3.2.3
Fluid Restriction
Fluid restriction can be a standard of care in both the core safety follow-up component 
and the optional tolvaptan treatment component of the trial.
The option of initiating fluid restriction (all fluids) to 1 liter/day for tolvaptan-treated 
subjects with serum sodium < 130 mEq/L (mmol/L) is available at the investigator’s 
discretion.  Fluid restriction (limit per day) will be recorded (if available and applicable)
on the electronic case report form (eCRF).
Fluid restriction must not be initiated for at least the first 24 hours after tolvaptan 
administration in order to determine the rate and magnitude of serum sodium change.  A 
supplemental serum sodium assessment is scheduled 8 (−1 to + 0.25) hours following the 
first dose of tolvaptan to provide additional information which may be used to guide the 
decision to initiate fluid restriction in the future.
3.3
Trial Population
3.3.1
Core Safety Follow-up Component
Approximately 100 male or female subjects will be enrolled in this trial.  All subjects 
must have participated in a previous tolvaptan pediatric hyponatremia trial.  
All subjects will be observed for safety for 6 months regardless of treatment status.
Subjects enrolled in the core safety component may be eligible to receive optional 
tolvaptan treatment during the 6-month core safety component (see Appendix 5 for 
optional tolvaptan treatment component eligibility requirements).
3.3.2
Optional Tolvaptan Treatment Component
Subjects enrolled in the core safety follow-up component of the trial may be eligible for 
treatment with tolvaptan. These subjects include, but are not limited to, those diagnosed 


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and admitted to a hospital for treatment of heart failure, hepatocellular disease (including 
cirrhosis), or SIADH/other.  Subjects with acute hyponatremia or hyponatremia expected 
to resolve spontaneously will be ineligible for tolvaptan treatment.  Children with an 
impaired ability to sense or communicate their thirst will either be required to undergo 
closer observation, laboratory and urine output monitoring, or will be ineligible for 
tolvaptan treatment if this is not possible.  Children with hypovolemic hyponatremia or 
those who are at risk of such, secondary to any underlying conditions that cause volume 
depletion, are ineligible for tolvaptan treatment.
Hyponatremia Etiology in Children and Adolescents
Children with Factor V Leiden or Factor VII abnormalities may be eligible for treatment 
only if the benefit is judged to outweigh any risk. Tolvaptan may be administered to 
children with hepatocellular disease (including cirrhosis) who have platelet counts
between 50,000 and 100,000/L if the need to treat is felt to outweigh the increased risk 
of GI bleeding.
Children can develop symptomatic hyponatremia more frequently than adults and at less 
severe levels of hyponatremia because of the large brain volumes in relatively small 
skulls.  The most serious consequence of hyponatremia is hyponatremic encephalopathy, 
which occurs in over 50% of children with serum sodium < 125 mmol/L.21
Hyponatremic encephalopathy is seen in hospitalized children and adolescents in 
association with SIADH or in the postoperative period.  Hyponatremic encephalopathy is 
a medical emergency that requires immediate intervention;4,22,23 thus, subjects with 
known risk factors for developing hyponatremic encephalopathy may be ineligible for 
tolvaptan treatment (eg, hypoxia, infection, brain injury, neurosurgery, uncontrolled 
seizure disorders, cerebritis, encephalopathy, central nervous system disorders such as 
cytotoxic and vasogenic cerebral edema, unstable space-occupying brain lesion, or 
elevated AVP levels).
Symptoms include headache, nausea and vomiting, weakness, confusion, altered 
consciousness, and lethargy and may progress to more advanced symptoms, including 
seizures, coma, and death, if untreated.  Subjects with overt symptoms of hyponatremia 
that require immediate intervention to raise serum sodium acutely will be ineligible for 
tolvaptan treatment; this syndrome is rapidly reversible with hypertonic saline 
administration.
Additionally, those subjects who are at risk of developing cerebral demyelination will be 
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120 mEq/L (mmol/L), hypernatremia, hypoxemia, severe liver disease, alcoholism, 
severe burns, severe malnutrition, hypokalemia, diabetes, or renal failure.4,21
Subjects eligible for treatment with tolvaptan will be identified based on serum sodium 
concentrations that persist at levels < 130 mEq/L (mmol/L).  Upon determination of 
eligibility, each subject’s serum sodium will be reassessed just before tolvaptan 
administration to confirm it remains below this threshold prior to intended treatment 
initiation.
If any serum sodium value obtained during the pretreatment baseline period for tolvaptan 
treatment is ≥130 mEq/L (mmol/L), the subject will be ineligible for tolvaptan 
administration at that time.  
3.4
Eligibility Criteria
3.4.1
Informed Consent/Assent
A written informed consent form (ICF) and assent, as appropriate, will be freely obtained 
from the subject’s parent or legal guardian, as applicable for local laws, in accordance 
with requirements of the trial center’s institutional review board/independent ethics 
committee (IRB/IEC).  The subject, as required by the trial center’s IRB/IEC, must 
provide informed consent/assent at baseline, and as such must be able to understand that 
he or she can 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.
Age-appropriate assent documents will be created and subjects who are able will be 
required to reconsent or assent as appropriate if they matriculate from one age group to 
another.  Subjects who became legal adults during the trial will be required to provide 
written informed consent as soon as they reach legal age.
Consent and assent will be documented on a written ICF and written informed assent 
form.  The ICF/assent will be approved by the same IRB/IEC that approves this protocol.  
Each ICF/assent will comply with the International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline24 and local regulatory requirements.  The 
investigator will review any written site-specific ICF/assent used in the trial, prior to 
submission to the IRB/IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject and his/her family without first obtaining consent and assent, as applicable.  
However, informed consent/assent (as applicable) must be obtained and documented 
prior to initiation of any procedures that are performed solely for the purpose of 
determining eligibility for this trial, including withdrawal from current medication(s).  


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Investigators may discuss this trial while the subject is still enrolled in the previous 
tolvaptan trial, however, consent and assent should not be obtained until the subject is 
ready to enroll into this trial at the baseline visit.  All informed consent/assent procedures 
must be in accordance with the trial center’s IRB/IEC and local regulatory requirements.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject and his/her parent or legal guardian by the investigator 
(or a qualified designee), and it has been documented that the subject and his/her parent 
or legal guardian has had the opportunity to ask questions, the IRB/IEC-approved written 
ICF/assent will be signed and dated by both the subject’s parent or legal guardian and the 
person obtaining consent (investigator or designee), as well as by any other parties 
required by the IRB/IEC.  In addition, the subject, as required by the trial center’s 
IRB/IEC, must provide ICF/assent by signing the appropriate form.  The subject’s parent 
or legal guardian will receive a copy of the signed ICF and assent form (as applicable); 
the originals shall be kept on file by the investigator.
Subjects’ parents or legal guardian(s) may be asked to sign additional ICFs if the protocol 
is amended to significantly add or change procedures.  Subjects may be asked to re-assent 
as appropriate if the protocol is amended to significantly add or change procedures.
3.4.2
Inclusion Criteria
Subjects invited to participate in the core safety follow-up component of the trial must 
satisfy all ICF/assent requirements, as well as meet all the following inclusion criteria
(Table 3.4.2-1):
Table 3.4.2-1
Inclusion Criteria for Core Safety Follow-up Component
1.
Enrollment in a previous tolvaptan pediatric trial for hyponatremia
2.
Trial-specific written informed consent/assent obtained from a parent/guardian or legally acceptable 
representative, as applicable for local laws, prior to the initiation of any protocol-required procedures.  
In addition, the subject must provide informed assent at baseline and must be able to understand that 
he or she can withdraw from the trial at any time
3.
Ability to comply with all requirements of the trial
4.
Willingness to be clinically followed for 6 months
Inclusion criteria for the optional tolvaptan treatment component are outlined in 
Appendix 5.
3.4.3
Exclusion Criteria
There are no exclusion criteria for entry into the core safety follow-up component of this 
trial.


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Exclusion criteria for the optional tolvaptan treatment component are outlined in 
Appendix 5. 
3.5
Outcome Variables
3.5.1
Primary Outcome Variable
Data for the primary efficacy variable will be collected for all subjects receiving 
tolvaptan in the optional tolvaptan treatment component of the trial, and will be 
summarized as follows:

Change from baseline in serum sodium while tolvaptan is being administered
3.5.2
Secondary Outcome Variables
3.5.2.1
Efficacy Variables
Data for the secondary efficacy variables will be collected for all subjects receiving 
tolvaptan in the optional tolvaptan treatment component of the trial and will be 
summarized as follows:

Percentage of subjects who require rescue therapy while on tolvaptan

Percentage of subjects who have recurrence of hyponatremia while on tolvaptan

Percentage of subjects requiring continuation of tolvaptan following 30 days of 
treatment
Additionally, for all subjects, the following variable will be assessed and summarized:

Change from baseline in QoL assessments (monthly for subjects on tolvaptan)
3.5.2.2
Safety Variables
Safety variables listed below and their differences from baseline will be summarized.
The safety variables are the following:

Frequency of AE reports (including cases of dehydration)

Changes from baseline in growth percentiles by visit for body height and weight

Tanner Staging progression score (at 6 months)
In addition to the safety variables reported for all subjects, the following variables will be
assessed for subjects who enter the optional tolvaptan treatment component of the trial:

Percentage of subjects with overly rapid correction in serum sodium (12 mEq/L 
([mmol/L]) in 24 hours after the first dose at introduction or reintroduction of 
tolvaptan)

Changes from baseline in ALT, AST, BT and creatinine for subjects on tolvaptan


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3.5.2.3
Pharmacokinetic Variable: Optional Tolvaptan Treatment
Component

Plasma concentrations of tolvaptan and metabolites in subjects who have 
continued tolvaptan therapy for 8 consecutive weeks
One PK sample should be taken after 8 weeks of continuous treatment per cycle.  This 
may include a discontinuation of < 72 hours (up to 2 doses) during the Day 30 treatment 
interruption.
3.6
Measures to Minimize/Avoid Bias
No measures to minimize bias were implemented as this is an observational trial with an 
option for open-label treatment. 
3.7
Trial Procedures
3.7.1
Core Safety Follow-up Component
Enrollment in this trial should follow completion or discontinuation of the previous 
tolvaptan hyponatremia trial.  A lapse between completion of the previous tolvaptan 
hyponatremia trial and enrollment into this trial is permitted while enrollment is open.  
Parents or legal guardians will consent and subjects will assent (as applicable) at baseline.
The final laboratory assessments for LFTs from the previous tolvaptan trial can serve as
baseline laboratory assessments for this trial if the values are within the normal range,
and collected within 30 days of the baseline visit for this trial.  The last assessments in the 
previous tolvaptan trial will serve as the baseline assessments if collected within 30 days 
of enrollement into this trial.  Otherwise, assessments will be repeated if > 30 days have 
lapsed since the previous tolvaptan trial.
Subjects will be followed for 6 months, (utilizing telephone calls and/or clinical trial site
visits).  Telephone calls will be conducted with reliable informants, per investigator 
discretion; either the subject and/or the parent/legal guardian. 
Trial assessments and time points for the core safety follow-up component are 
summarized in Table 3.7.1-1 and described in Section 3.7.3.1.  


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Table 3.7.1-1
Core Safety Follow-up Component:  Schedule of Assessments for All Subjects
Procedures
Baseline
Month 1
(+2 Weeks)
Month 2
(+2 Weeks)
Month 3
(+2 Weeks)
Month 4
(+2 Weeks)
Month 5
(+2 Weeks)
Month 6 or 
Early 
Termination
(+2 Weeks)
Informed consent and assent
X
Review inclusion criteria
X
Demographic informationa
X
Telephone assessmentb
X
X
X
X
X
In-clinic assessment
X
X
Medical history
X
Hyponatremia historya
X
Vital signsa,c
X
X
Physical examinationa,d
X
X
Neurological examination
Xh
Body height/weight/growth percentiles
X
X
Tanner Staginga,e
X
X
ALT, AST, and BT
Xf
(X)f
(X)f
Quality of Life assessments
X
X
Vital statusg
X
Concomitant medications a,i
Adverse eventsa
aThe last assessments in the previous tolvaptan trial will serve as the baseline assessments if collected within 30 days of enrollment into this trial.  Otherwise, 
assessments will be repeated if > 30 days has lapsed since the previous tolvaptan trial.  For liver function tests, see footnote f.  
bTelephone calls can be replaced with clinical site visits.  Telephone calls will be conducted with reliable informants, per investigator discretion; either the 
subject and/or the parent/legal guardian.
cVital signs to be assessed include supine blood pressure, heart rate, respiratory rate, and temperature.  Vital signs should be assessed prior to any blood 
draws.


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dIf the physical examination was performed > 30 days prior to enrollement into this trial, or the baseline visit overlaps with the pretreatment baseline visit in 
the optional tolvaptan treatment component, a full physical examination will be performed at baseline.  A directed physical examination will be done at the 
core safety baseline visit if < 30 days has elapsed since the previous trial, and should be done at the Month 6/ET visit.  Physical examination should include 
a fontenelle assessment as age appropriate.
eA subject who reaches Stage 5 (both in pubic hair and genitalia) does not need to continue with Tanner Staging.
fIf the subject’s last LFT (AST, ALT or BT) was abnorrmal or the subject’s baseline visit occurred > 30 days after completion of the previous trial, the subject 
will be required to have LFTs assessed at baseline.  If the subject’s last LFTs were normal and the baseline visit occurred < 30 days after completion of the 
previous trial, LFTs will be collected at Month 1 or Month 2 (in-clinic visit or local laboratory).  
gVital status will be collected through telephone contact at Month 6 (+ 2 weeks) only for subjects who had an early termination and did not withdraw consent.  
hA full neurological examination will be completed at the baseline visit only if a full physical examination is performed (see footnote d).
iIf > 30 days has lapsed since the previous tolvaptan trial, medications taken with 30 days of enrollment will be recorded.


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3.7.2
Optional Tolvaptan Treatment Component
If a subject has a clinical need for tolvaptan, the subject may be screened for eligibility to 
be treated with tolvaptan (see Appendix 5).  To assess the subject’s eligibility to receive
tolvaptan, the subject must have been off treatment with IMP for 7 days following the 
end of treatment in the previous tolvaptan trial.
Subjects who meet the eligibility criteria for tolvaptan treatment will be administered 
tolvaptan based on age, weight, and the use of CYP3A4 inhibitors on Day 1 of the cycle.  
Subsequent dosing adjustments are based on serum sodium response.  Refer to 
Section 3.2.1.2 for dosing guidelines. 
Trial assessments and time points for the optional tolvaptan treatment component are 
summarized in Table 3.7.2-1 and described in Section 3.7.3.2.


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Table 3.7.2-1
Schedule of Assessments for Each Treatment Cycle
Proceduresa
Pre-
treatment 
Baselineb
Titration Phaseb
Post-titration
Treatment 
Cycle 
Month 2
Treatment 
Cycle Month 
3+
(Maintenance)
Month 6
(D173)
Cycle DC
(+ 2 wk)
Follow- up Phasek
Days 
-4 to -1
Day 
1
Day 
2 
and 
3
Day 
4
Day 
7, 
14 
and 
21
Day 
30 
(1)
Day 
31c
Day 
32c
Day 
33c
Day 
34c
every 2 
weeks 
(2 days)
Mth 2 Wk 2
(D47), Mth 
2 Wk 4
(D61)
Once monthly 
(2 days)
Mth 3 (D89), 
Mth 4 (D117), 
Mth 5 (D145)
24 
(4) 
hours 
post-
last 
dose
7 (1) 
days 
post-
last 
dose
14 
(2) 
days 
post-
last 
dose
Review 
eligibility 
criteria for 
treatment
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examinationd
X
X
X
Body height 
and weight/
growth 
percentiles
X
X
X
Pregnancy 
teste
X
X
X
X
X
Clinical status 
assessment
X
X
X
X
X
X
X
Neurological 
assessmentf
X
X
X
X
X
X
X
Quality of 
Life
assessment
X
X
Assess ALT, 
AST, BT, and 
creatinine
X
X
Xg
X
X
X
Assess serum 
sodiumh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 3.7.2-1
Schedule of Assessments for Each Treatment Cycle
Proceduresa
Pre-
treatment 
Baselineb
Titration Phaseb
Post-titration
Treatment 
Cycle 
Month 2
Treatment 
Cycle Month 
3+
(Maintenance)
Month 6
(D173)
Cycle DC
(+ 2 wk)
Follow- up Phasek
Days 
-4 to -1
Day 
1
Day 
2 
and 
3
Day 
4
Day 
7, 
14 
and 
21
Day 
30 
(1)
Day 
31c
Day 
32c
Day 
33c
Day 
34c
every 2 
weeks 
(2 days)
Mth 2 Wk 2
(D47), Mth 
2 Wk 4
(D61)
Once monthly 
(2 days)
Mth 3 (D89), 
Mth 4 (D117), 
Mth 5 (D145)
24 
(4) 
hours 
post-
last 
dose
7 (1) 
days 
post-
last 
dose
14 
(2) 
days 
post-
last 
dose
Tolvaptan 
dosing
X
Xi
Xi
X
X
X
X
X
X
Confirm 
stable dose
X
Dispense 
tolvaptan drug 
kit
X
X
X
X
X
Day 30 
treatment 
interruption
X
X
Tolvaptan 
collection/
reconciliation
X
X
X
X
X
PK sample 
collectionj
X
Xj
Telephone 
call
X
Concomitant 
medications
Adverse 
events
aAssessments that are part of a core safety follow-up component trial visit which happens to overlap with a visit in the optional tolvaptan treatment component 
only need to be performed once.


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bTitration can be up to 4 days.  Cycles can be repeated as needed during the 6-month core safety component.  If a subject is off tolvaptan treatment for ≥72 
hours, titration/reinitiation of tolvaptan will require reassessment of eligibility criteria and will begin in a hospital setting as part of a new treatment cycle.
cDuring the Day 30 treatment interruption, Days 31, 32, 33 and 34 must follow consecutively.  Once the Day 30 visit is determined, the subsequent visit days 
do not have a window.
dA full physical examination will be performed at the pretreatment baseline visit if it overlaps the day of the core safety component baseline visit.  Otherwise, 
a directed physical examination will be performed at the required visits.  A physical examination should include a fontanelle assessment as age appropriate.
eUrine or serum pregnancy tests will be performed on female subjects 12 years of age and female subjects < 12 years of age if menstruation has started.  In 
Treatment Cycle Month 2 a pregnancy test should be performed a month after the previous assessment at the Month 2, Week 4 visit.
fA full neurological examination will be completed at the first pretreatment baseline visit.  If the subject has any positive findings on any of the clinical status 
assessments, a full neurological examination can be performed per investigator judgment.
gIn Treatment Cycle Month 2, Week 4, liver function tests and serum creatinine should be collected and assessed.
hSerum sodium will be assessed for efficacy and safety (supplemental draws) according to Table 3.7.4.1.2-1.
iThe dose will be titrated based on serum sodium results assessed at a minimum of 24-hour intervals (4 hours).  See Section 3.2.1.2 for dosing information.
jOne PK sample should be taken after 8 weeks of continuous treatment per cycle.  This may include a discontinuation of < 72 hours during the Day 30 
treatment interruption.  A sample will only be collected at Month 3 if missed at the Month 2 visit.
kSubjects who discontinue or complete the treatment cycle should immediately proceed to the Follow-up Phase.


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3.7.3
Schedule of Assessments
3.7.3.1
Core Safety Follow-up Component
3.7.3.1.1
Baseline
Participation in this trial should follow completion or discontinuation of the previous 
tolvaptan trial.  The last assessments in the previous tolvalptan trial will serve as the 
baseline assessments if collected within 30 days of enrollment into this trial.  Otherwise, 
assessments will be repeated if > 30 days has lapsed since the previous tolvaptan trial.  
The following procedures will be performed during the baseline visit:
1) Trial procedures and information regarding the nature of the trial will be reviewed 
and written informed consent/assent will be obtained prior to any trial-related 
procedures.
a) ICF and assent will be obtained from each subject’s parent or legal guardian 
prior to any trial procedures being conducted.
b) Each subject will indicate willingness to participate in the trial by signing or 
marking an assent form (as applicable) supplied for this purpose.
c) Informed consent/assent needs to be obtained each time a subject matriculates 
into the next age group.
2) Inclusion criteria for entry into the core safety follow-up component will be 
reviewed and documented.
3) Demographic information will be collected or transferred from the previous trial.
4) Medical and hyponatremia history will be recorded separately.  Medical history 
should include the subject’s current list of medical problems in addition to the 
history recorded for the prior trial.  The hyponatremia medical history should 
include the etiology of subject’s hyponatremia (see Section 3.3.2) and what 
treatment was administered before trial enrollment.  A detailed history specific to 
etiology of hyponatremia will also be recorded.
5) Any observable symptoms of hyponatremia will be assessed and recorded 
separately.
6) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
transferred from the last assessments from the previous trial or assessed after the 
subject has been supine for 3 minutes, as appropriate.  Vital signs should be 
performed prior to the blood draws.
7) Physical examination information will be transferred from the last assessments 
from the previous trial or performed, as appropriate.  Physical examination should 
include a fontenelle assessment as age appropriate.  
8) A neurological examination will be conducted.  A full neurological examination 
will be completed if a full physical examination is performed.
9) Body height and body weight will be measured.
10) Growth percentile will be calculated.  Prior growth development information 
should also be collected, if available.


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11) Tanner Staging will be transferred from the last assessments from the previous 
trial or completed as part of the physical examination, as appropriate.  Historical 
staging information should also be collected, if available. A subject who has 
reached Stage 5 (both in pubic hair and genitalia) does not need to continue with 
Tanner Staging.
12) If the subject’s last LFT (AST, ALT or BT) was abnormal or the subject’s 
baseline visit occurred > 30 days after completion of the previous trial, the subject 
will be required to have LFTs assessed at baseline.  If the subject’s last LFTs were 
normal and the baseline visit occurred < 30 days after completion of the previous 
trial, LFTs will be collected at Month 1 or Month 2.
13) Quality of Life assessment will be performed, as appropriate by age and where 
available.
14) Concomitant medications will be recorded.  If > 30 days have lapsed since the 
previous tolvaptan trial, medications taken within 30 days of enrollment will be 
recorded.
15) Adverse events will be assessed.
3.7.3.1.2
Months 1, 2, 3, 4, and 5
Subjects and/or their parents or legal guardians will be contacted by telephone at the end 
of Months 1, 2, 3, 4, and 5 (+ 2 weeks) to assess any new or ongoing AEs and to collect 
information on any medications administered since the last visit.
If the subject’s last LFTs were normal and the baseline visit occurred < 30 days after 
completion of the previous trial, LFTs will be collected at Month 1 or Month 2 (in-clinic 
visit or local laboratory).
3.7.3.1.3
Month 6/Early Termination
Subjects will return to the clinical trial site at the end of Month 6 (+ 2 weeks) or at early 
termination (ET) and the following assessments will be performed:
1) Any observable symptoms of hyponatremia will be assessed and recorded 
separately.
2) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
performed prior to any blood draws.
3) A directed physical examination will be performed.  Physical examination should 
include a fontenelle assessment as age appropriate.
4) Body height will be measured.
5) Body weight will be measured.
6) Growth percentile will be calculated.


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7) Tanner Staging will be completed at the Month 6 clinical trial site visit or at ET
according to the instructions specified in Section 3.7.5.6 and Appendix 4. A 
subject who has reached Stage 5 (both in pubic hair and genitalia) does not need 
to continue with Tanner Staging.
8) Quality of Life assessment will be performed, as appropriate by age and where 
available.
9) Concomitant medications will be recorded.
10) Adverse events will be assessed.
Month 6 is the completion visit, and subjects will no longer be eligible for optional 
tolvaptan treatment under this protocol at this time.
If a subject terminates early from the trial and agrees to continued telephone contact, the 
subject or parent/legal guardian will be contacted by telephone at Month 6 to assess vital 
status.
3.7.3.2
Optional Tolvaptan Treatment Component
Subjects may become eligible for tolvaptan treatment at any time while participating in 
the 6-month core safety follow-up component if they have dilutional (euvolemic or 
hypervolemic) hyponatremia (serum sodium < 130 mEq/L [mmol/L]).  The investigator 
is required to call the medical monitor to discuss the appropriateness of tolvaptan 
treatment for subjects who discontinued from the previous trial of titrated oral IMP early 
or demonstrated a lack of response to tolvaptan, but have a demonstrated clinical need for 
tolvaptan.  Subjects participating in the optional tolvaptan treatment component will 
concurrently maintain visit assessments in the core safety follow up component up to and 
including the Month 6 final visit.  Core safety follow-up assessments can be scheduled 
per the defined windows and at the convenience of the subject’s optional tolvaptan 
treatment visit schedule.  
Since hyponatremia in this patient population can often be transient and/or may be 
secondary to hypovolemic states, potential subjects will be screened for hyponatremic 
histories as well as clinically evaluated to exclude such cases from the optional tolvaptan 
treatment component of the trial. To be eligible for the optional tolvaptan treatment 
component of this protocol, subjects must have persistent dilutional (euvolemic or 
hypervolemic) hyponatremia, defined as serum sodium assessments < 130 mEq/L 
(mmol/L) that are documented for at least 48 hours after the final dose of IMP in the 
previous trial and prior to the planned initiation of tolvaptan titration in this trial.  These 
values can be documented using historical values previously obtained per standard of 
care.  A third (immediate [STAT]) serum sodium assessment < 130 mEq/L (mmol/L), 
which will serve as the final treatment qualification, management strategy, and baseline 


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value for efficacy endpoints, is to be obtained within 2 to 4 hours prior to the first dose of 
tolvaptan.  Additional qualification assessments will be performed per etiology of 
hyponatremia (Section 3.3.2).
The procedures to be performed at the required visits for subjects in need of tolvaptan 
treatment and for each tolvaptan treatment cycle are summarized in this section.
If possible, all assessments while subjects are treated with tolvaptan should be 
synchronized with those performed as part of the core safety follow-up component of the 
trial (ie, assessments should not be performed twice at the same time point).
3.7.3.2.1
Pretreatment Baseline Visit
The following procedures will be performed during the pretreatment baseline visit
(Days −4 to −1) to ensure the subject qualifies for each tolvaptan treatment cycle:
1) Eligibility criteria (see Appendix 5) will be reviewed.
2) A clinical status assessment including a full neurological examination will be 
performed.  If the subject has any positive findings on the clinical status 
assessment at the second or subsequent pretreatment baseline visits, a full 
neurological examination can be performed per investigator judgment.
3) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed at each visit after the subject has been supine for 3 minutes.  Vital 
signs should be performed prior to the blood draws.
4) A full physical examination will be performed if it overlaps with the same 
assessment at the core safety baseline visit.  Otherwise, a directed physical 
examination will be performed. Physical examination should include a fontenelle 
assessment as age appropriate. 
5) Body height will be measured.
6) Body weight will be measured.
7) Growth percentile will be calculated.
8) A blood sample for ALT, AST, BT and creatinine will be collected.
9) A urine or serum pregnancy test will be performed on female subjects 12 years 
of age and female subjects < 12 years of age if menstruation has started.
10) Within 48 hours prior to tolvaptan administration, 2 samples for serum sodium 
testing will be collected at least 12 hours apart.
11) Quality of Life assessment will be performed, as appropriate by age and where 
available.
12) Concomitant medications will be recorded.
13) Adverse events will be assessed.


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3.7.3.2.2
Titration Phase 
A subject who requires tolvaptan treatment can be treated for as many cycles as deemed 
necessary by the investigator within the 6 month trial period.  The duration of treatment 
cycles may vary per the investigator’s assessment of clinical need. Regardless of the 
number of treatment cycles and the duration of tolvaptan treatment in each cycle, optional 
tolvaptan treatment cycles will consist of a titration phase, a maintenance phase, and a 
follow-up phase.  The schedule of assessments for the optional tolvaptan treatment 
component is shown in Table 3.7.2-1.
The first dose of tolvaptan will be administered upon successful completion of all 
pretreatment baseline procedures.  Subjects will enter a titration phase and follow the 
titration schedule outlined in Section 3.2.1.2.  Subjects will be required to be in a hospital 
setting during initiation and titration of tolvaptan. 
During the Titration Phase on Day 1 up to Day 4 of treatment, in addition to serum 
sodium samples obtained for treatment qualification and efficacy endpoints, supplemental 
samples for the purposes of safety assessment will be obtained using a point of care 
(POC) sodium assessment unit, where available, at 4 to 6 (+0.25) hours postdose and at 
18 (± 1) hours postdose.  A POC assessment unit is preferred; however, regular blood 
draws may be used (especially if they can be combined with standard of care labs).  A 
schedule of blood samples required for serum sodium assessments can be found in Table 
3.7.4.1.2-1.
3.7.3.2.2.1
Day 1
All titration of tolvaptan will be done in a hospital setting.  Please see Section 3.2.1 for 
details on titration and dosing.
The following procedures will be performed on Day 1:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A blood sample for STAT serum sodium testing will be collected within 2 to 4
hours prior to the first dose.  Results need to be reviewed prior to dosing to 
confirm continued treatment eligibility of the subject.
3) In addition to serum sodium samples obtained for treatment qualification and 
efficacy endpoints, supplemental samples for the purposes of safety assessment 
only will be obtained using a POC sodium assessment unit, where available, on 
Day 1 at 4 to 6 (+0.25) hours postdose and at 18 (± 1) hours postdose.  A POC
assessment unit is preferred; however, regular blood draws may be used 
(especially if they can be combined with standard of care labs).
4) Tolvaptan will be administered.


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5) A blood sample for serum sodium testing will be collected 8 (-1 to +0.25) hours 
post-first dose.
6) Concomitant medications will be recorded.
7) Adverse events will be assessed.
Table 3.7.4.1.2-1 presents the efficacy and safety serum sodium samples required during 
Day 1 of the titration period.
3.7.3.2.2.2
Day 2 up to Day 4
The investigator should schedule evaluations daily while the subject remains in a hospital 
setting per the schedule of assessments.  The following procedures will be performed 
during the titration period:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A blood sample for serum sodium testing must be assessed at 24 (4) hours post-
dose (trough) on Days 2, 3, and 4.  The results must be reviewed prior to
tolvaptan dosing.
3) In addition to serum sodium samples obtained for treatment qualification and 
efficacy endpoints, supplemental samples for the purposes of safety assessment 
will be obtained using a POC sodium assessment unit, where available, at 6 (-1 to 
+0.25) hours postdose and at 18 (± 1) hours postdose on Days 2, 3, and 4 during
the titration period.  A POC assessment unit is preferred; however, regular blood 
draws may be used (especially if they can be combined with standard of care 
labs).
4) Administer tolvaptan.  Tolvaptan will be titrated per the titration guidelines (see 
Section 3.2.1.2).
4) On Day 4, if a stable dose of tolvaptan has been confirmed, the initial titration 
phase will conclude, and sufficient tolvaptan will be dispensed for subjects that 
are outpatients for QD dosing until their next scheduled visit.  Subjects and their 
parents/legal guardians will be instructed to return any remaining tolvaptan at the 
next visit for dose reconciliation.
6) Concomitant medications will be recorded.
7) Adverse events will be assessed.
8) Instruct subjects not to take a tolvaptan dose before coming to the clinic for their 
Day 7 visit.
Table 3.7.4.1.2-1 presents the efficacy and safety serum sodium samples required during 
Days 2, 3, and 4 of the titration period.


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3.7.3.2.3
Days 7, 14, and 21
Subjects should arrive to the clinic prior to taking the morning dose of tolvaptan. The 
following assessments will be performed during each in-clinic visit during the first month 
of the treatment cycle:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A blood sample for serum sodium testing must be assessed at 24 (4) hours post-
last dose with the results reviewed prior to subsequent tolvaptan dosing.
3) Tolvaptan will be administered.  
4) Tolvaptan dispensed at each visit will be returned for accountability.
5) Sufficient tolvaptan will be dispensed for subjects that are outpatients for QD
dosing until their next scheduled visit.  Subjects and their parents/legal guardians
will be instructed to return any remaining tolvaptan at the next visit for dose 
reconciliation.
6) Concomitant medications will be recorded.
7) Adverse events will be assessed.
8) Instruct subjects not to take a tolvaptan dose before coming to the clinic for their
Day 14, 21, and 30 visits.
Once the Day 30 visit is scheduled, the next visits (Days 31 to 34) must occur 
consecutively. 
3.7.3.2.4
Day 30 Interruption: 30 (1) Days Post-first Dose
After 30 days of tolvaptan treatment, all subjects (exceptions explained in 
Section 3.1.2.1) should discontinue treatment for up to 2 doses to assess the continued 
need for tolvaptan treatment.  Subjects should arrive to the clinic prior to taking the 
morning dose of tolvaptan.
The following assessments will be performed during the Day 30 visit:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A blood sample for serum sodium testing must be assessed at 24 (4) hours post-
last dose with the results reviewed prior to subsequent tolvaptan dosing.
3) A blood sample for ALT, AST, BT, and creatinine will be collected.
4) Tolvaptan dispensed the previous week will be returned for accountability.
5) Tolvaptan will be administered during the clinic visit.
6) Concomitant medications will be recorded.
7) Adverse events will be assessed.


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8) Instruct subjects to return to the clinic for visits on Day 31 and 32.
3.7.3.2.4.1
Day 31
The following assessments will be performed:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A clinical status assessment will be performed.  If the subject has any positive 
findings on the clinical status assessment, a full neurological examination can be 
performed per investigator judgment.
3) A blood sample will be collected for serum sodium testing at 24 hours (± 4 hours) 
post the Day 30 dose.  Refer to Figure 3.1-1 for a trial schematic, and 
Section 3.2.1 for a description of the treatment continuation decision.
4) Concomitant medications will be recorded.
5) Adverse events will be assessed.
3.7.3.2.4.2
Day 32
The following assessments will be performed:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A clinical status assessment will be performed.  If the subject has any positive 
findings on the clinical status assessment, a full neurological examination can be 
performed per investigator judgment.
3) A blood sample will be collected for serum sodium testing at 48 hours (± 4 hours) 
post the Day 30 dose.  Refer to Figure 3.1-1 for a trial schematic and Section 3.2.1
for a description of the treatment continuation decision.
4) Concomitant medications will be recorded.
5) Adverse events will be assessed.
3.7.3.2.4.3
Day 33
The following assessments will be performed:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A clinical status assessment will be performed.  If the subject has any positive 
findings on the clinical status assessment, a full neurological examination can be 
performed per investigator judgment.


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3) A urine or serum pregnancy test will be performed on female subjects 12 years 
of age and female subjects < 12 years of age if menstruation has started.
4) A blood sample will be collected for serum sodium testing at 72 hours (± 4 hours) 
post the Day 30 dose.  Refer to Figure 3.1-1 for a trial schematic and Section 3.2.1
for a description of the treatment continuation decision.
5) Confirm need for continuing treatment.
a) If continuing treatment is needed and subjects have been off drug for < 72
hours:

Tolvaptan will be administered.
Subjects who reinitiate treatment at the same dose or a lower dose of 
tolvaptan after discontinuation for < 72 hours will not be required to 
reinitiate treatment in a hospital setting. However, tolvaptan will not be 
dispensed until subjects have a 24 hour postdose serum sodium assessment
on Day 34.  
b) If continuing treatment is needed and subjects have been off drug for ≥72 
hours:

Subjects will reinitiate treatment, starting with titration (Section 3.2.1.2),
which will require reassessment of the eligibility criteria. Titration will
begin in a hospital setting as part of a new treatment cycle starting at the 
pretreatment baseline visit (Section 3.7.3.2.1).  In these cases, the subject 
will re-start the schedule of assessments at the pretreatment baseline visit.
c) If no continuing treatment is needed:

The subject will move to the Follow-up Phase visit schedule and complete 
the assessments for the 7-day and 14-day post-last dose visits (Section 
3.7.3.2.7.2).
6) Concomitant medications will be recorded.
7) Adverse events will be assessed.
3.7.3.2.4.4
Day 34
The following assessments will be performed:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A clinical status assessment will be performed.  If the subject has any positive 
findings on the clinical status assessment, a full neurological examination can be 
performed per investigator judgment.
3) A blood sample will be collected for serum sodium testing at 24-hours (± 4 hours) 
post last dose (trough) with the results reviewed prior to a subsequent tolvaptan 
dose.
4) Tolvaptan will be administered.
5) Sufficient tolvaptan will be dispensed for subjects that are outpatients for QD
dosing until their next scheduled visit.  Subjects and their parents/legal guardians 


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will be instructed to return any remaining tolvaptan at the next visit for dose 
reconciliation.
6) Concomitant medications will be recorded.
7) Adverse events will be assessed.
8) Instruct subjects not to take a tolvaptan dose on the day of the next scheduled 
visit.
3.7.3.2.5
Treatment Cycle Month 2: Month 2 Week 2 and Month 2 Week 
4 (2 days)
The next clinic visit should occur 2 weeks after the decision to continue treatment is 
made (Month 2 Week 2, Day 47 [± 2 days]), and then 2 weeks thereafter if treatment is 
continued (Month 2 Week 4, Day 61 [± 2 days]).  Subjects should arrive to the clinic 
prior to taking the morning dose of tolvaptan.  
The following assessments will be performed during each visit during the second month 
of each treatment cycle:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A blood sample for serum sodium testing must be assessed at 24 (4) hours post-
last dose (trough) with the results reviewed prior to subsequent tolvaptan dosing.
3) A blood sample for ALT, AST, BT and creatinine will be collected (Month 2 
Week 4 visit only).
4) For each treatment cycle, a single PK blood sample will be collected after 8 
consecutive weeks of tolvaptan dosing for the determination of tolvaptan and 
metabolites plasma concentrations.
5) A clinical status assessment will be performed.  If the subject has any positive 
findings on the clinical status assessment, a full neurological examination can be 
performed per investigator judgment.
6) A urine or serum pregnancy test will be performed at each visit on female subjects 
12 years of age and female subjects < 12 years of age if menstruation has started
(Month 2 Week 4 visit only).
7) Tolvaptan dispensed the previous visit will be returned for accountability.
8) Tolvaptan will be administered in clinic.
9) Sufficient tolvaptan will be dispensed for subjects that are outpatients for QD
dosing until their next scheduled visit.  Subjects and their parents/legal guardians 
will be instructed to return any remaining tolvaptan at the next visit for dose 
reconciliation.
10) Concomitant medications will be recorded.
11) Adverse events will be assessed.


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12) Instruct subjects not to take a tolvaptan dose on the day of the next scheduled 
visit.
3.7.3.2.6
Maintenance Phase
3.7.3.2.6.1
Treatment Cycle Month 3 (and every month thereafter)
(2 days)
Subjects will return to the clinical trial site for assessment once monthly for Month 3 
(Day 89 [± 2 days]), Month 4 (Day 117 [± 2 days]), Month 5 (Day 145 [± 2 days]) and 
Month 6 (Day 173[± 2 days]).  Subjects should arrive to the clinic prior to taking the 
morning dose of tolvaptan.  The following procedures will be performed:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for ≥ 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A urine or serum pregnancy test will be performed at each visit on female subjects 
12 years of age and female subjects < 12 years of age if menstruation has started
(Months 3, 4, and 5).
3) A directed physical examination will be performed. Physical examination should 
include a fontenelle assessment as age appropriate.
4) Body height will be measured (Months 3, 4, and 5).
5) Body weight will be measured (Months 3, 4, and 5).
6) Growth percentile will be calculated (Months 3, 4, and 5).
7) A clinical status assessment will be performed.  If the subject has any positive 
findings on the clinical status assessment, a full neurological examination can be 
performed per investigator judgment (Months 3, 4, and 5).
8) A blood sample for ALT, AST, BT, and creatinine will be collected.
9) A blood sample for serum sodium testing will be collected at 24 hours (± 4 hours) 
post-last dose (trough).
10) Tolvaptan dispensed the previous month will be returned for accountability.
11) Tolvaptan will be administered in the clinic (Months 3, 4, and 5).
12) Sufficient tolvaptan will be dispensed for subjects that are outpatients for QD
dosing until their next scheduled visit.  Subjects and their parents/legal guardians 
will be instructed to return any remaining tolvaptan at the next visit for dose 
reconciliation.
13) A single PK blood sample will be collected if missed at Month 2 and there have
been 8 weeks of consecutive tolvaptan treatment.
14) Quality of Life assessments will be performed, as appropriate by age and where 
available (Months 3, 4, and 5).
15) Concomitant medications will be recorded.
16) Adverse events will be assessed.


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17) Instruct subjects not to take a tolvaptan dose on the day of the next scheduled visit
(Months 3, 4, and 5).
Tolvaptan treatment cycles may be repeated at the discretion of the investigator during 
subject’s participation in the 6-month core safety period. After discontinuation of 
tolvaptan for any reason, subjects will proceed to the Follow-up Phase as noted in 
Section 3.7.3.2.7.
3.7.3.2.7
Follow-up Phase
After discontinuation from tolvaptan treatment, the subject must return to the site for 
follow-up assessments at 24 (4) hours post-last dose (if applicable) and/or at 7 (1)
days post-last dose.  A follow-up telephone contact will occur at 14 (±2) days post-last 
dose. 
If a subject starts a new treatment cycle during the Follow-up Phase, the remaining 
follow-up visits will not be done and the subject will restart at the pretreatment baseline 
visit.
3.7.3.2.7.1
First Follow-up: 24 (4) Hours Post-last Dose
The following procedures will be performed:
1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A blood sample for ALT, AST, BT, and creatinine will be collected.
3) A urine or serum pregnancy test will be performed on female subjects 12 years 
of age and female subjects < 12 years of age if menstruation has started (if not 
done within the last 30 days).
4) A blood sample for serum sodium testing will be collected at 24 (4) hours post-
last dose.
5) Any remaining tolvaptan will be collected from the subjects and returned for 
accountability.
6) Concomitant medications will be recorded.
7) Adverse events will be assessed.
3.7.3.2.7.2
Second Follow-up: 7 (1) Days Post-last Dose
An additional follow-up visit will occur 7 (1) days post-last dose. The following 
assessments will be performed:


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1) Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be 
assessed after the subject has been supine for 3 minutes.  Vital signs should be 
assessed prior to blood draws.
2) A blood sample for serum sodium testing will be collected.
3) Concomitant medications will be recorded.
4) Adverse events will be assessed.
3.7.3.2.7.3
Third Follow-up: 14 (2) Days Post-last Dose
A follow-up telephone contact will occur at 14 (2) days post-last dose for assessment of 
AEs and concomitant medications.
1) Concomitant medications will be recorded.
2) Adverse events will be assessed.
Subjects will complete the remaining visits in the core safety follow-up component up to 
Month 6.
3.7.4
Efficacy Assessments
3.7.4.1
Serum Sodium Concentrations
3.7.4.1.1
Serum Sodium Samples for Efficacy
Serum sodium samples for assessment of efficacy will be collected during the optional 
tolvaptan treatment component of the trial according to Table 3.7.4.1.2-1.
Additional details can be found in Section 3.7.3.2.
3.7.4.1.2
Supplemental Sodium Samples for Safety
In addition to serum sodium samples obtained for treatment qualification and efficacy 
endpoints, supplemental samples for the purposes of safety assessment only will be 
obtained using a POC sodium assessment unit, where available. A POC assessment unit 
is preferred; however, regular blood draws may be used (especially if they can be 
combined with standard of care labs).  The supplemental sodium samples for safety 
assessments are found in Table 3.7.4.1.2-1.


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Table 3.7.4.1.2-1
Serum Sodium Assessments During the Optional Tolvaptan 
Component
Blood Draws for Serum Sodium
Treatment 
Cycle
Phase
Day
Efficacy 
Supplemental Safety
Month 1
Pretreatment
baseline 
-4 to -1
Within 48 hours prior to 
tolvaptan administration, 2 
blood samples, 12 hours 
apart
-
Titration
1
2 to 4 hours prior to the first 
dose
-
8 (-1 to + 0.25) hours 
postdose
4 to 6 (+ 0.25) hours 
postdose
-
18 (± 1) hours postdose
2, 3, and 4
24 (± 4) hours post previous 
dose (trough)
6 (-1 to +0.25) hours and 18 
( ±1) hours postdose
Posttitration 
treatment
7, 14 and 
21
24 (± 4) hours post previous
dose
-
Day 30 
interruption
30
24 (± 4) hours post previous 
dose
-
31
24 (± 4) hours post previous
dose
32
48 (± 4) hours post previous
dose
-
33
72 (± 4) hours post previous
dose
-
34
24 (± 4) hours post previous
dose
-
Month 2
Treatment 
Every 14 
(± 2) days
24 (± 4) hours post previous
dose
-
Months 3, 
4 and 5
Treatment
(Maintanence)
Every 
month (± 2 
days)
24 (± 4) hours post previous
dose
-
Month 
6/ET
Trial 
termination
-
Month 6 or trial termination
-
Follow-up
Follow-up
-
24 (± 4) hours post-previous
dose
-
-
7 (±1) days post last dose
-
Additional details can be found in Section 3.7.3.2.
3.7.4.1.3
Unscheduled Assessments
Additional unscheduled serum sodium assessments or supplemental sodium assessments
(POC) may be performed at the discretion of the clinical investigator and other 
physicians of record, depending on the local standards and subject’s clinical condition.  
Unscheduled sodium assessments will only be collected if associated with an AE.


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3.7.4.2
Quality of Life Assessments
Two patient-reported outcomes instruments (acute versions with 7 day recall period) will 
be used to assess subject quality of life: PedsQL Generic Core Scale and PedsQL 
Multidimensional Fatigue Scale.  Both instruments are appropriate for 2 years of age, 
however availability may be limited for certain ages and languages.  The age groups 
covered by these assessments are Toddler (2–4 years), Young child (5–7 years), Child 
(8–12 years), and Adolescent (13–18 years).  Depending on the subject’s age, the 
questionnaire may be completed by either the subject or the parent/caregiver, as 
appropriate.

The PedsQL Generic Core Scale consists of 23 items encompassing 
physical, emotional, social, and school domains.  

The PedsQL Multidimentional Fatigue Scale consists of 18 items in 3 
subscales:  general fatigue, sleep/rest fatigue, and cognitive fatigue.  The 
instrument focuses on the domains of processing speed, 
attention/vigilance, visual and working memory.  
3.7.5
Safety Assessments
Safety will be assessed through the monitoring of AEs, clinical laboratory tests, vital 
signs, body weight, physical examinations, neurological examinations, rescue therapy, 
fluid restriction, and Tanner Staging.  See Table 3.7.1-1 and Table 3.7.2-1.
The monitoring frequency of safety assessments is at the discretion of the clinical 
investigator; however, the trial requires the minimum sample collection for all subjects 
noted in Section 3.7.5.2.
3.7.5.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
In addition, for subjects on tolvaptan treatment, active monitoring is required for:

Absolute serum sodium level 145 mEq/L (mmol/L)

An overly rapid correction of the serum sodium level (an increase in serum 
sodium of > 8 mEq/L [mEq/L (mmol/L)] over a 10-hour period, 12 mEq/L 
[mEq/L (mmol/L)] over a 24-hour period, or a rate of correction in serum sodium 
concentration that the investigator deems too rapid)

Neurologic symptoms, or other signs or symptoms suggestive of osmotic 
demyelination (see Section 5.3.1 for more details)

Elevations in AST or ALT that are 2 ULN or levels that increase 2 times 
their previously observed level.  If this occurs, a BT level should also be 


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evaluated.  See Section 3.7.5.3.1 for more information and Section 5.4 for detailed 
instructions on how this type of event should be captured

Worsening symptoms of hyponatremia

Hypovolemia or hypotension requiring intervention.

Clinical signs and symptoms of dehydration
3.7.5.2
Clinical Laboratory Tests: Core Safety Follow-up Component
Table 3.7.5.2-1 presents the protocol-required clinical laboratory tests for all subjects 
enrolled in the core safety follow-up component. No further laboratory assessments are 
required per protocol except as needed for the follow-up of AEs.
Table 3.7.5.2-1
Clinical Laboratory Tests During Core Safety Follow-up
AST
ALT
BT
3.7.5.3
Clinical Laboratory Tests: Optional Tolvaptan Treatment
Component
Table 3.7.5.3-1 presents the protocol-required clinical laboratory tests for all subjects in 
the optional tolvaptan treatment component. If these laboratory tests are to be obtained 
as part of the standard of care for the subject, the timing should be coordinated per the 
schedule of assessments (Section 3.7.3), whenever possible, to minimize the number of 
blood draws for the subject. All clinical laboratory tests required during optional 
tolvaptan treatment will be performed by local laboratories.  For the schedule of 
laboratory assessments, please refer to Appendix 6.
Table 3.7.5.3-1
Clinical Laboratory Tests During Optional Tolvaptan 
Treatment
ALT
AST
BT
Creatinine
Efficacy:
Serum Sodium
Additional Tests:
Serum or urine pregnancy test (if applicable)
Supplemental sodium samples for safety
3.7.5.3.1
Monitoring of Liver Transaminases
Long-term use of tolvaptan has demonstrated the potential to cause a clinically significant 
elevation in liver function test values. Based on previous research in the adult polycystic 
kidney disease population, the expected onset of the elevation, if it occurs, is between 
3 and 14 months of chronic treatment with tolvaptan.


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For a subject who experiences an elevation in AST or ALT that is 2 ULN or whose 
levels increase 2 times their previous observed value, a total bilirubin (BT) level should 
also be evaluated.  These elevated values should be confirmed by retesting.  If BT is 2
ULN or 2 times their previous observed value, an immediately reportable event (IRE) 
form with all values listed should be completed and also reported as an AE on the eCRFs.  
See Section 5.4.1 for detailed instructions on how this type of event should be captured.
3.7.5.4
Physical Examination and Vital Sign Assessments
Full and directed physical examinations will be performed and documented according to 
the Schedule of Assessments (Section 3.7.3).  If the physical examination was performed 
> 30 days prior to enrollment into this trial or the core safety baseline visit overlaps with 
the pretreatment baseline visit in the optional tolvaptan treatment component, a full 
physical examination will be performed.  A directed physical examination will be done at 
the core safety baseline visit if < 30 days have elapsed since the previous trial.  A directed 
physical examination will also be performed at the Month 6/ET visit.
The principal investigator or his/her appointed designee is primarily responsible to 
perform the physical examination.  If the appointed designee is to perform the physical 
examination, he/she must be permitted by local regulations.  Whenever possible, the 
same individual should perform all physical examinations.  Any condition present at the 
posttreatment directed physical examination that was not present at baseline should be 
documented as an AE and followed to a satisfactory conclusion.
Full physical examination assessments should include assessments of all major body 
systems, including but not limited to, ears, nose, and throat, the thorax area, abdomen, 
urogenital, extremities, and skin and mucosae. Directed physical examinations should be 
focused on hyponatremia-related signs and symptoms as well as any major changes from 
baseline.  Physical examination will include a fontanelle assessment as age appropriate.
Body weight will be measured (see Schedule of Assessments Section 3.7.3).  Every effort 
should be made to ensure that body weight measurements will be performed in a 
reproducible and consistent manner.  Body weight measurements should be performed at 
the clinical trial site always using the same scale.  Subjects should wear the same type of 
clothes at each measurement, preferably a gown and no shoes.  All body weight 
measurements should be taken post void.
Vital sign data will include supine blood pressure, heart rate, respiratory rate, and 
temperature.  Vital signs will be taken when the subject has been lying down (bed 
positioned < 45 degree angle) for at least 3 minutes.  All vital sign assessments should be 
performed prior to the blood draw at the nominal time point.


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3.7.5.5
Neurological Examination
A neurological examination will be performed as part of the directed physical 
examination per the Schedule of Assessments in Table 3.7.1-1 and Table 3.7.2-1.  It will 
include an evaluation of mental status, cranial nerves, muscle tone, muscle strength 
symmetry, reflexes, neonatal primitive reflexes, sensory system, gait and finger to nose, 
as age appropriate.  
A full neurological examination will be completed at the core safety baseline visit only if 
a full physical examination is being performed, or at the first pretreatment baseline visit.  
If the subject has any positive findings on any of the clinical status assessments, a full 
neurological examination can be performed per investigator judgment. 
The principal investigator or his/her appointed designee is primarily responsible to 
perform the full neurological examination.  If the appointed designee is to perform the 
full neurological examination, he/she must be permitted by local regulations.
3.7.5.6
Tanner Staging
The collection of Tanner Staging data is required for all subjects in the core safety 
follow-up component at the baseline and the Month 6 Visit. Every attempt should be 
made to collect this information. 
Tanner Staging must be completed together with the physical examination by the same 
trial affiliated clinician in the most inconspicuous manner for the subject as possible.  
Tanner Staging may be completed by the trial affiliated pediatrician or family practitioner 
(additionally physician’s assistant or nurse practitioner where licensing permits).  A 
subject who reaches Stage 5 (both in pubic hair and genitalia) does not need to continue 
with Tanner Staging, and the same stage will be carried forward to any subsequent visits.  
Sites should make attempts to have examiners of both sexes.  Attempts should be made to 
have the examination performed by the same sex personnel as the subject.  Otherwise, 
trial-affiliated personnel of the same sex as the subject (ie, nurse) should be in the same 
examination room as the subject.
Tanner Staging assessment consists of 2 domains (pubic hair and breast development) for 
girls and 3 domains (pubic hair, penis development, and testes development) for boys.  
The Tanner Staging assessment as a reference for the completing clinician is included in 
Appendix 4.  The clinician will arrive at a single score summarizing the domains (not 
individual domain scores) when evaluating the subject.


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3.7.5.7
Hyponatremia History
Each subject’s hyponatremia medical history will be recorded at the baseline visit of the 
core safety follow-up component.  The hyponatremia history should include the etiology 
of subject’s hyponatremia and what treatment was administered before trial enrollment.  
Symptoms potentially attributable to hyponatremia should be specifically assessed for in 
prior history.  The hyponatremia assessment at baseline will consist of documentation of 
hyponatremia etiology (eg, SIADH, hepatocellular disease [including cirrhosis], heart 
failure, or other) and prior hyponatremia treatment, ie, fluid restriction, if applicable.  A 
detailed history specific to etiology of hyponatremia will also be recorded.
3.7.5.8
Clinical Status Assessment
Clinical status assessments will be performed per inpatient standard of care and should 
include review of patient chart entries, including hyponatremia assessment notes, trial-
and nontrial-specific laboratory results, any examination findings, medical problem list 
changes, and fluid intake and output to evaluate overall subject eligibility in terms of 
hyponatremia state. The clinical assessment will focus on symptoms and signs which 
will inform treatment decisions (eg, the need to switch to rescue therapy, or the ability to 
safely discharge a subject from the hospital). The clinical assessment should be 
performed by a trial investigator who will be aware of laboratory and other clinical 
response data.
3.7.5.9
Vital Status
An assessment of vital status will be conducted on subjects who terminate prior to the 
Month 6 core safety visit, and do not withdraw consent for continued telephone contact.  
The telephone contact will be made on the date at which the subject would have reached 
the core safety follow-up component Month 6 visit (+ 2 weeks), and will be conducted 
with a reliable informant; either the subject and/or the parent/legal guardian, per 
investigator discretion.  Vital status collected and recorded will be:

Subject alive

Subject deceased (date of death, cause of death)
3.7.6
Pharmacokinetic Assessments
3.7.6.1
Blood Collection Times
For subjects undergoing treatment with tolvaptan for at least 8 consecutive weeks (short 
interruptions of < 72 hours are still considered consecutive treatment), a single blood 
sample to measure tolvaptan and metabolite concentrations at steady state will be 


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obtained for each treatment cycle.  The date and time of the PK sample and the date and 
time of the dose given immediately prior to the PK sample will be documented and 
recorded on the eCRF.
For each subject all samples will be collected according to local guidelines and best 
practices for pediatric care.
3.7.6.2
Sample Handling and Processing
All blood samples will be shipped to the testing facility for analysis.  Specific 
information regarding sample handling and processing is provided in Appendix 3.
3.7.7
End of Trial
The End of Trial Date is defined as the last date of contact or the date of final contact 
attempt from the Month 6 visit or early termination visit for the last subject completing or 
withdrawing from the trial.
3.7.8
Independent Data Monitoring Committee
An independent data monitoring committee (IDMC) has been established for this trial.  
This committee will meet on a regular basis to ensure the safe and ethical treatment of 
trial subjects, ensure the scientific integrity of the trial, and to ensure the trial is 
conducted within the bounds of ethical medical practice.  It may make recommendations 
to the sponsor and trial steering committee to amend or terminate the trial based on 
grounds of safety, futility, or greater than expected efficacy as defined by the accepted 
statistical practices and procedures to be detailed in their charter.  The specific duties of 
the IDMC will be detailed in a separate IDMC charter document.
3.8
Stopping Rules, Withdrawal Criteria and Procedures
3.8.1
Entire Trial or Treatment Component(s)
If the sponsor terminates or suspends the trial for safety or unanticipated other reasons, 
prompt notification will be given to investigators, IRBs/IECs, 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/IEC if judged to be necessary for medical, safety, regulatory, ethical or other 
reasons consistent with applicable laws, regulations, and Good Clinical Practice (GCP).  
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/IEC at the site.


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3.8.3
Individual Subject Discontinuation
If a subject discontinues from the trial prematurely, the reason must be fully evaluated 
and recorded appropriately in source documents and the eCRF.  If the subject is being 
withdrawn because of an AE, that AE should be indicated as the reason for withdrawal.
All subjects have the right to withdraw at any point during the trial without prejudice. 
The investigator can discontinue a subject’s participation in the trial at any time if 
medically necessary.  In addition, subjects meeting the following criteria must be 
withdrawn from tolvaptan treatment:
a) Occurrence of any AE, intercurrent illness, or abnormality in a laboratory 
assessment which, in the opinion of the investigator, warrants the subject’s 
permanent withdrawal of tolvaptan treatment;
b) Treatment with a prohibited concomitant medication other than the use of 
appropriate medications for the treatment of AEs under direction of the 
investigator;
c) Subject noncompliance, defined as refusal or inability to adhere to the trial
schedule or procedures (see Section 3.12, Subject Compliance);
d) At the request of the subject, investigator, Otsuka Pharmaceutical 
Development & Commercialization, Inc. (OPDC) or designee, or regulatory 
authority;
e) Subject becomes pregnant; or
f)
Subject is lost to follow-up.
In addition, subjects on tolvaptan treatment who meet the following criteria should have 
results confirmed with a repeat test. Sodium tests should be done either STAT or through 
bedside monitoring.

The subject’s serum sodium increases by > 8 mEq/L (mmol/L) in any 10-hour 
period following dosing on Day 1 of a cycle

The subject’s serum sodium increases by 12 mEq/L (mmol/L) in the 24-hour 
period following dosing

At any time after dosing, the subject’s serum sodium is 145 mEq/L (mmol/L).

Evidence of dehydration

Abnormal liver function tests (see Section 5.4)
If the result is confirmed, the medical monitor should be contacted to consider options of 
down-titration, dose discontinuation, concomitant medication adjustment, fluid 
supplementation, and/or withdrawal.  


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The sponsor and the medical monitor should be notified promptly when a subject requires 
IV normal saline or other rescue therapy.  Subjects receiving rescue therapy are to 
continue to be monitored per protocol (to discharge or death).  Subjects who have 
received rescue therapy secondary to inadequate response to tolvaptan will not be 
allowed to reinitiate tolvaptan treatment.
The investigator will notify the sponsor promptly when a subject is withdrawn.
When a subject or parent/legal guardian or legally responsible representative decides to 
withdraw from the trial they will be asked to indicate whether they wish to discontinue 
from the trial as a whole, or still allow telephone contact.  If they agree to continued 
telephone contact, they will be contacted at Month 6 for vital status (Section 3.7.5.9).
3.9
Screen Failures
Since the core component of this trial is a 6-month safety follow-up trial, no subject will 
be considered a screen failure.
3.10
Definition of Completed Subjects
The core safety follow-up component of the trial is defined as the time period during 
which subjects are evaluated for primary and/or secondary objectives of the trial
regardless of whether or not the subject was on tolvaptan treatment.  For purposes of this 
trial, subjects who complete the Month 6 visit in the core safety component will be 
defined as trial completers.
The opportunity to participate in the optional tolvaptan treatment component is open to 
subjects during their 6-month participation in the core safety component.
3.11
Definition of Lost to Follow-up
Subjects or subjects’ parents/guardians who cannot be contacted on or before their final 
visit prior to the trial termination date, who do not have a known reason for 
discontinuation (eg, withdrew consent or AE), and for whom a current health status at the 
end of the trial cannot be determined will be classified as “lost to follow-up” as the 
reason for discontinuation.  Current health status can be determined from a variety of 
sources, either by obtaining acceptable documentation for death (ie, death certificate, 
medical records, public records, or statement by a family member or primary care 
physician) or acceptable documentation for life (ie, direct contact with the subject, 
medical records, successful telephone call with the subject, statement by a family 
member or primary care physician, or public records).  It is expected that 3 documented 
attempts will be made to determine a subject’s current health status before assigning a 
“lost to follow-up” status.


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3.12
Subject Compliance
For the core safety follow-up component compliance is defined as completion of all 
visits.
For the optional tolvaptan treatment component compliance will be ensured by watching 
the subject take his/her tolvaptan while the subject is hospitalized or during clinical trial 
site visits.  For nonclinical trial site days, compliance will be assessed by the number of 
tablets remaining when the subject returns the blister cards at the next visit.  This 
information will be recorded on the appropriate eCRF and on the Drug Accountability
Forms.
3.13
Protocol Deviations
In the event of a significant deviation from the protocol because of an emergency, 
accident, or mistake (eg, violation of informed consent/assent process, tolvaptan 
dispensing or subject dosing error, treatment assignment error, or subject enrolled in 
violation of eligibility criteria or concomitant medication criteria), the investigator or 
designee will contact INC Research 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
During tolvaptan treatment, continuous or short term use of other medications, while not 
prohibited, may be restricted by the investigator because of their potential for interference 
with tolvaptan metabolism.  Since tolvaptan is a sensitive CYP3A4 substrate, subject 
dosing will be determined based on weight, age and use of CYP3A4 inhibitors.  Refer to 
Section 3.2.1 for dosing guidelines.  A partial list of CYP3A4 inhibitors is provided in 
Table 4.1-1.


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Table 4.1-1
List of Cytochrome P450 3A4 Inhibitors (Partial List)
boceprevir
nefazodone
clarithromycin
nelfinavir
clotrimazole (oral)
posaconazole
conivaptan
ritonavir
indinavir
saquinavir
itraconazole
telaprevir
ketoconazole
telithromycin
lopinavir
voriconazole
mibefradil
4.2
Other Restrictions
The ingestion of pomelo, grapefruit, grapefruit juice, products containing Seville oranges, 
and St. John’s Wort is prohibited from 72 hours prior to dosing with tolvaptan until 
24 hours post-last dose of tolvaptan.  In addition, the use of alcohol within 72 hours prior 
to dosing and during tolvaptan treatment is prohibited.
The use of saline in this population should be closely monitored.  The use of hypertonic 
saline (3% or greater) within 8 hours of the initial screening laboratory collection prior to 
tolvaptan treatment is prohibited.  The use of hypertonic saline (3% or greater) is 
prohibited during tolvaptan treatment.  Routine use of hypertonic saline, while prohibited, 
may be considered only if used emergently (ie, with a severe symptomatic episode) and 
with the understanding that free water clearance may be stimulated if tolvaptan had been 
administered in the prior 24 hours, based on the medical judgment of the investigator.  
Please see Section 4.1 for the partial list of prohibited medications during tolvaptan 
treatment.  The use of normal saline (0.9%) is allowed during the Pretreatment baseline
Period until the beginning of treatment; normal saline use can resume during the follow-
up period.  Subjects should no longer be on maintenance fluids containing normal saline 
during treatment with tolvaptan.  Subjects may be administered IV solutions containing 
hypotonic saline (eg, half-normal [0.45%] saline) if necessary, for fluid management.  
The medical monitor should be contacted at any point if questions arise regarding the use 
of saline during the trial.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as medical 


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history at screening for pre-planned procedures for which the underlying condition was 
known and no worsening occurred.  An adverse reaction is any untoward and inintended 
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.  For the purpose of Investigational New Drug (IND) safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal 
relationship between the IMP and the AE.  Suspected adverse reaction implies a lesser 
degree of certainty about causality.
A serious adverse event (SAE) includes any event that results in any of the following 
outcomes:
1) Death
2) Life-threatening, ie, the subject was, in the opinion of the investigator or 
sponsor, 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.
3) Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions
4) Requires in-patient hospitalization or prolongs hospitalization

Hospitalization itself should not be reported as an SAE; wherever possible 
the reason for hospitalization should be reported

Hospitalization or prolonged hospitalizations for social admissions (ie, 
those required for reasons of convenience or other non-medical need) are 
not considered SAEs
5) Congenital anomaly/birth defect
6) 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.
Non-serious adverse events are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event:

Any SAE

Any AE related to occupational exposure

Potential Drug Induced Liver Injury (DILI) case (see Section 5.4)

Pregnancies are also defined as IREs.  Although normal pregnancy is not 
an AE, it will mandate IMP discontinuation and must be reported on an 


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IRE form to OPDC.  Pregnancy will only be documented on the AE eCRF 
if there is an abnormality or complication.
Clinical Laboratory Changes:  It is the investigator’s responsibility to review the results 
of all laboratory tests as they become available.  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 eCRF.  The intensity of an AE is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality:  Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related:
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related:  There is no temporal or causal relationship between the IMP and 
the AE.
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 yesterday/last time we spoke?”  All AEs (serious and nonserious) reported by 
the subject must be recorded on the source documents and eCRFs provided by INC 
Research.  Serious AE collection is to begin after a subject has signed the ICF/assent.
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 


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an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
In addition, INC Research must be notified immediately by telephone or fax of any 
Immediately Reported Events (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 within 24 hours after either the investigator or 
site personnel become aware of any SAE, DILI, or confirmed pregnancy, by telephone or 
by fax to INC Research as outlined in Appendix 1.  An IRE form must be completed and 
sent by fax or overnight courier to INC Research.  (Please note that the IRE form is NOT 
the AE eCRF.)
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal, or have otherwise been 
explained.  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 
INC Research.
5.3.1
Hyponatremia-related Adverse Events
5.3.1.1
Rapid Correction of Serum Sodium
When tolvaptan is not administered with adequate fluid intake, overly rapid correction of 
serum sodium may occur.  Rapid correction of serum sodium level may lead to osmotic 
demyelination syndrome, a condition that can lead to severe brain damage and even 
death.  Age-appropriate neurological examinations will be performed during 
administration of tolvaptan to monitor changes in health status in addition to serum 
sodium.  This protocol is designed to provide adequate vigilance during the 
administration of tolvaptan to ensure that overly rapid correction does not occur in this 
pediatric population.
Rapid correction of hyponatremia is defined as any increase in serum sodium 
12 mEq/L (mmol/L)/24 hours.  If this change is observed during the trial, it should be
reported as an IRE following the instructions detailed in Section 5.3.


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5.3.1.2
Other Hyponatremia-related Adverse Events
Other events related to hyponatremia should be monitored closely and reported as 
appropriate depending on their severity:

Absolute serum sodium level 145 mEq/L

Any increase in serum sodium > 8 mEq/L [mmol/L] over a 10-hour period

Neurological symptoms or other signs or symptoms suggestive of osmotic 
demyelination

Worsening symptoms of hyponatremia

Hypovolemia or hypotension requiring intervention

Signs and symptoms of dehydration
All AEs must be monitored until symptom resolution or until the condition stabilizes.
5.4
Potential Drug-induced Liver Injury
For a subject who experiences an elevation in AST or ALT that is 2 ULN or whose 
levels increase 2 times their initial baseline value, a BT level should also be evaluated.  
Elevated values should be confirmed via retest.  If the BT is 2 ULN or 2 times their 
baseline value, an IRE form should be completed with all values listed and also should be 
reported as an AE on the eCRFs.
If hepatic injury is suspected, tolvaptan should be promptly discontinued, appropriate 
treatment should be instituted, and investigations should be performed to determine 
probable cause.  Such an event should be reported and followed until resolution.
5.4.1
Liver Transaminase Elevations
Management of abnormal liver function test results should be based on the investigator’s 
clinical judgment.  A liver function test result that is 2 ULN is generally accepted as a 
medically significant occurrence across various medical disciplines.
For a subject that experiences an elevation in AST or ALT that is 2 ULN or whose 
levels increase 2 times their initial baseline value in subjects with an elevated baseline 
value, a BT level should also be evaluated.  If the BT is 2 ULN or 2 times their 
baseline value in subjects with an elevated baseline value, an IRE form with all values 
listed should be completed and also reported as an AE on the eCRFs.


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The following guideline for repeat testing may be used by investigators as a reference for 
any subject with an ALT or AST 2 ULN:
1) ALT, AST, alkaline phosphatase, and BT should be repeated within 48 to 
72 hours (needed to confirm abnormalities and determine if they are 
increasing or decreasing).
2) Inquiries should be made about symptoms (fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, and/or rash) and signs like jaundice, 
yellowish discoloration of sclera, etc.
3) If discharged or transferred, the subjects should be retested locally and results 
given to the investigator immediately, along with that laboratory’s normal 
ranges.
4) Close observation is required if symptoms persist or repeat testing shows ALT 
or AST 3 ULN for subjects with normal baseline measures OR 2-fold 
increases above baseline values for subjects with elevated values before drug 
exposure.  If close monitoring is not possible, the drug should be interrupted 
until such monitoring is possible or the drug should be permanently 
discontinued.
5) All trial subjects with evidence of possible DILI should be followed until all 
abnormalities return to normal or to the baseline state.
Close observation may involve:
1) Repeating liver enzymes and serum bilirubin tests 2 or 3 times weekly.
2) Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize or if the trial drug has been interrupted/discontinued and the subject 
is asymptomatic.
3) Obtaining a more detailed history of symptoms and prior or concurrent 
diseases.
4) Obtaining a history of concomitant drug use (including non-prescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, special diets, and change in diet.
5) Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
alcoholic hepatitis, nonalcoholic steatohepatitis; hypoxic/ischemic 
hepatopathy; and biliary tract disease.
6) Obtaining a history of exposure to environmental chemical agents.
7) Obtaining additional tests to evaluate liver function, as appropriate (eg, 
international normalized ratio [INR], direct bilirubin).
8) Considering gastroenterology or hepatology consultations.


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5.4.1.1
Criteria for Discontinuation from the Optional Tolvaptan 
Treatment Component of the Trial due to Liver Transaminase 
Elevations
A subject must be discontinued from tolvaptan treatment on confirmation of any of the 
following criteria:
1) ALT or AST 8 ULN
2) ALT or AST 5 ULN for more than 2 weeks
3) ALT or AST 3 ULN AND (BT 2 ULN or INR > 1.5)
4) ALT or AST 3 ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) and 
signs of jaundice
If there is any question about how to proceed with a particular subject’s case, do not 
hesitate to contact your regional medical monitor to discuss treatment options.  The FDA 
has issued a guidance for industry regarding this topic.  This guidance is not specific to 
hyponatremia.  Otsuka is integrating many of the recommendations in this guidance into 
all of its clinical research programs.  Links to this guidance and information from the 
FDA regarding drug-induced liver injury are provided in the references.25,26
5.5
Pregnancy
Women of childbearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 12 
months).
For WOCBP and for males who are sexually active, 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 optional tolvaptan 
treatment component of this 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 remains fully 
abstinent (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation 
methods] or withdrawal are not acceptable methods of contraception), 2 of the following 
precautions must be used:  vasectomy, tubal ligation, vaginal diaphragm, intrauterine 
device, birth control pills, birth control depot injection, birth control implant, condom
with spermicide, or sponge 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.


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Before enrolling WOCBP in the optional tolvaptan treatment component of this clinical 
trial, investigators must review the below guidelines about trial participation with all 
WOCBP.  The topics should generally include:

General information

ICF/assent form, as applicable

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment in the optional tolvaptan treatment component, WOCBP must be 
advised of the importance of avoiding pregnancy during trial participation and the 
potential risk factors for an unintentional pregnancy.  The subject or the subject’s parent 
or legal guardian must sign an ICF/assent stating that the above-mentioned risk factors 
and the consequences were discussed with the subject and/or the parent/guardian.
For WOCBP who are participating in the optional tolvaptan treatment component, a urine 
and/or serum pregnancy test for human chorionic gonadotropin (hCG) will be performed 
at pretreatment baseline on all WOCBP (and female subjects ≥12 years of age and all 
female subjects < 12 years of age, if menstruation has started).  Urine and/or serum 
pregnancy tests will also be conducted at Day 33 and monthly thereafter. If a urine test is 
performed and is positive, the investigator will follow up with a confirmatory serum test.
During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available.  If the 
pregnancy is confirmed, the subject must not receive the IMP and must not be enrolled in
the optional tolvaptan treatment component of this trial.  If pregnancy is suspected while 
the subject is taking IMP, the IMP must be withheld immediately (if reasonable, taking 
into consideration any potential withdrawal risks) until the result of the pregnancy is 
known.  If pregnancy is confirmed, the IMP will be permanently discontinued in an 
appropriate manner (eg, dose tapering if necessary for subject safety) and the subject will 
be withdrawn from the trial.  (Exceptions to trial discontinuation may be considered for 
life-threatening conditions only after consultations with INC Research [see Appendix 1
for contact information])


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The investigator must immediately notify the INC Research 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 INC Research.  INC Research will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy.
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray trials).  Other appropriate 
pregnancy follow-up procedures should be considered, if indicated.  In addition, the 
investigator must report to INC Research, 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 as this is an open-label trial.
5.7
Follow-up of Adverse Events
For subjects in the core safety follow-up component of this trial, information on AEs will 
be followed for 2 weeks after the Month 6 Visit.
5.7.1
Follow-up of Non-serious Adverse Events
Non-serious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status noted.  If a subject has not recovered from the AE at the 
last scheduled contact, follow-up contacts will be scheduled at least every 4 weeks until 
reolution of the AE is confirmed or the condition is considered clinically stable. All non-
serious events that are ongoing at the last scheduled contact will be recorded as ongoing 
on the eCRF.  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).
5.7.2
Follow-up of Serious Adverse Events
This trial requires that subjects be actively monitored for SAEs up to 14 days after the 
last dose of IMP is administered, or 14 days after the Month 6/ET visit, whichever is 
later.
Serious adverse events that are identified or ongoing on the last scheduled contact
must be recorded on the AE eCRF page and reported to INC Research according to the 
reporting procedures outlined in Section 5.3.  This may include unresolved previously 


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reported SAEs or new SAEs.  The investigator will follow SAEs until the events are 
resolved, stabilized, or the subject is lost to follow-up.  Resolution means 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.  The 
investigator will continue to report any significant follow-up information to INC 
Research up to the point the event has been resolved.
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 tolvaptan, should be reported to INC Research.  This may include SAEs 
that are captured on follow-up telephone call or at any other time point after the defined 
trial period (ie, up to last scheduled contact).  The investigator should follow serious 
related AEs 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 INC Research up to the point the event has been 
resolved or stabilized.
6
Pharmacokinetic/Pharmacodynamic Analysis
6.1
Pharmacokinetic Analysis
For those subjects undergoing chronic treatment with tolvaptan for at least 8 consecutive 
weeks for each initiation or reinitiation of therapy, the concentration of tolvaptan and 
metabolites will be obtained and summarized using descriptive statistics.
7
Statistical Analysis
7.1
Sample Size
Sample size was not determined by a formal computation to achieve a target power.  It is 
expected that approximately 100 subjects may enroll from previous tolvaptan pediatric 
trials for hyponatremia.
7.2
Datasets for Analysis
The following datasets are defined for this trial:

Enrolled Subjects (core safety follow-up component)


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
Core Dataset:  comprises all subjects for whom an ICF is signed for 
the trial.

Treated Subjects (optional tolvaptan treatment component)

Safety Dataset:  comprises those subjects who receive at least one dose 
of tolvaptan.

Efficacy Dataset:  comprises those subjects in the safety dataset who 
have at least one post-baseline efficacy evaluation for serum sodium 
concentration.
7.3
Handling of Missing Data
The primary dataset for efficacy analyses will be in the tolvaptan treated subjects -
efficacy dataset.  The efficacy dataset will consist of the actual observations recorded at 
each visit so that no imputation of missing values will be made.
7.4
Primary and Secondary Outcome Analysis
7.4.1
Primary Outcome Analysis
The primary endpoint for all tolvaptan treated subjects is:

Change from baseline in serum sodium while tolvaptan is being administered
7.4.2
Secondary Outcome Analyses
The secondary endpoints for all tolvaptan treated subjects include the following:

Percentage of subjects who require rescue therapy while on tolvaptan

Percentage of subjects who have recurrence of hyponatremia while on tolvaptan

Percentage of subjects requiring continuation of tolvaptan following 30 days of 
treatment

Percentage of subjects with overly rapid correction in serum sodium (12 mEq/L 
[mmol/L]) in 24 hours after the first dose at introduction or reintroduction of 
tolvaptan

Changes from baseline in ALT, AST, BT and creatinine for subjects on tolvaptan
In addition, the secondary endpoints for all enrolled subjects include:

Frequency of AE reports

Change from baseline in QoL assessments

Change from baseline in growth percentiles by visit for body height and weight

Tanner Staging progression score (at 6 months)


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All secondary endpoints will be summarized using descriptive statistics.
7.4.3
Interim Analysis
No interim analysis is planned.
7.5
Analysis of Demographic and Baseline Characteristics
Demographic characteristics and medical history at baseline will be summarized by 
descriptive statistics, eg, proportion, mean, median, standard deviation, minimum, and 
maximum values.
7.6
Safety Analyses
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 for all subjects (AEs), and all subjects receiving tolvaptan (treatment-
emergent AEs [TEAEs]):

AEs and TEAEs

AEs and TEAEs by severity

TEAEs potentially causally related to the IMP

AEs and TEAEs with an outcome of death

Serious AEs and TEAEs

AEs and TEAEs leading to discontinuation
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
7.6.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the clinical laboratory measurements 
will be provided.  Potentially clinically significant results in laboratory tests will also be 
summarized.  Shift tables will be produced for assessing changes from baseline in clinical 
laboratory measurements in low-normal-high scale.  Where baseline values are 
unavailable, summary statistics of available data at each visit will be presented.
7.6.3
Physical Examination and Vital Signs Data
In general, summary statistics for changes from baseline in vital signs will be provided.  
Potentially clinically significant results in vital signs will also be summarized.  No 


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analysis will be performed on physical examination data.  Physical examination data will 
be listed.
8
Management of Investigational Medicinal Product
For full details on tolvaptan management, please refer to the tolvaptan IB.  
8.1
Packaging and Labeling
Trial medication will be provided to the investigator(s) by the sponsor (or designated 
agent).  Tolvaptan will be supplied as 3.75-, 7.5-, 15-, and 30-mg spray-dried tablets.  
Each package used in the dosing period will be labeled to clearly disclose the 
subject identification (ID), compound ID, trial number, the sponsor’s name and address, 
instructions for use, route of administration, appropriate precautionary statements, and 
other information required by local regulatory authorities.
The current tolvaptan tablet formulation intended for use in the optional tolvaptan 
component of this trial is limited to administration to those who can easily swallow a 
3.75-mg tablet (6 mm) and weigh 10 kg.
8.2
Storage
Tolvaptan will be stored in a securely locked cabinet or enclosure.  Access will be limited 
to the investigators and their designees.  Neither investigators nor any designees may 
provide tolvaptan to any subject not participating in this protocol.
Tolvaptan will be stored at 25C (77F) or below, with excursions allowed from 15C to 
30C (59F to 86F).  The clinical trial site staff or designated personnel will maintain a 
temperature log in the drug storage area recording the temperature at least once each 
working day.
8.3
Accountability
The investigator, or designee, must maintain an inventory record of tolvaptan received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused and/or partially used tolvaptan
must be returned to OPDC (or a designated contractor).
All tolvaptan returned to OPDC must be accompanied by the appropriate documentation 
and be clearly identified by protocol number and trial site number on the outermost 


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shipping container.  Returned supplies should be in the original containers.  The assigned 
trial monitor should facilitate the return of unused and/or partially used tolvaptan.
8.5
Reporting of Product Quality Complaints
A product quality complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate, or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of a drug 
product or medical device after it is released for distribution.  Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of IMP from the sponsor through and including reconciliation and up to 
destruction, including subject dosing.  The investigator or designee must notify the 
sponsor (or sponsor’s designee) within 24 hours of becoming aware of the PQC by e-mail 
or telephone and according to the procedure outlined below.

Online – Send information required for reporting purposes (listed below) to 

Phone - Rocky Mountain Call Center at 
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 complaint

Reporter identification (eg, subject, investigator, site)
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
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 
the complaint sample is available for return, return it in the product retrieval package, 
which will be provided by Otsuka America Pharmaceutical, Inc.-Ethics, Quality and
Compliance (OAPI-EQC).
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to OAPI-EQC for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by OAPI EQC-QM group.
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 investigators and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
During each subject’s visit to the clinical trial site, a clinician participating in the trial will 
record progress notes to document all significant observations.  At a minimum, these 
notes will contain:


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
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 tolvaptan 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 tolvaptan 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 trial 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 
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 promptly 
and LEGIBLY transcribed to eCRFs for transmission to the sponsor.  Changes 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 investigator 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 investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.


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9.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods:

A period of at least 2 years following the date on which approval to market the 
drug is obtained (or if tolvaptan development is discontinued, the date regulatory 
authorities were notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities; OR

Longer, region-specific storage requirements, if applicable.
The investigator 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 investigator 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.  
If the investigator withdraws from the trial (eg, because of relocation or retirement), all 
trial-related records should be transferred to a mutually agreed upon designee within a 
sponsor-specified timeframe.  Notice of such transfer will be given to the sponsor in 
writing.
10
Quality Control and Quality Assurance
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws.  As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications.  In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented.


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10.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, tolvaptan supply, presence of required 
documents, the informed consent process, and comparison of eCRFs 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, the ICH GCP Guideline
(E6), international ethical principles derived from the Declaration of Helsinki and 
Council for International Organizations of Medical Sciences (CIOMS) guidelines, and 
applicable local laws and regulations.  Each trial site will seek approval/favorable opinion
by an IRB or IEC according to regional requirements, and the investigator will provide 
that documentation to the sponsor.  The IRB/IEC will evaluate the ethical, scientific, and 
medical appropriateness of the trial.  Further, in preparing and handling CRFs, the 
investigator, subinvestigator, and their staff will take measures to ensure adequate care in 
protecting subject privacy.  To this end, a subject number and subject identification code 
will be used to identify each subject.
Financial aspects, subject insurance, and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
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 supplies of tolvaptan, 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.


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Subjects will be identified only by unique subject numbers in eCRFs.  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/IEC.  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/IEC, as required by local 
regulations.  Except for “administrative” or “non-substantial” amendments, investigators 
will wait for IRB/IEC 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 the tolvaptan tablets used in the trial.  A protocol change intended to 
eliminate an apparent immediate hazard to subjects should be implemented immediately
after agreement by the sponsor and investigator, followed by IRB/IEC notification within 
local applicable timelines.  The sponsor will submit protocol amendments to the 
applicable regulatory agencies within local applicable timelines.
When the IRB/IEC, 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/IEC, 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 
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2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.


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15
References
1
Totapally BR, Raszynski A. Hyponatremia in pediatric practice. Int Pediatrics. 
2006;21(1):37-50.
2
Eulmesekian PG, Perez A, Minces, PG, Bohn D. Hospital-acquired hyponatremia in 
postoperative pediatric patients: Prospective observational study. Pediatr Crit Care 
Med. 2010;11(4):479-83.
3
Hanna M, Saberi MS. Incidence of hyponatremia in children with gastroenteritis 
treated with hypotonic intravenous fluids. Pediatr Nephrol. 2010;25:1471-5.
4
Moritz ML, Ayus JC. New aspects in the pathogenesis, prevention, and treatment of 
hyponatremic encephalopathy in children [Review]. Pediatr Nephrol. 
2010;25(7):1225-38.
5
Adrogue HJ. Consequences of inadequate management of hyponatremia. Am J 
Nephrol. 2005;25:240-9.
6
Miller M, Morley JE, Rubenstein LZ. Hyponatremia in a nursing home population. J 
Am Geriatr Soc. 1995;43(12):1410-3.
7
Schrier RW. Pathogenesis of sodium and water retention in high-output and low-
output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy. (Second of two 
parts). N Engl J Med. 1988;319(17):1127-34.
8
Chen L-K, Lin M-H, Hwang S-J, Chen T-W. Hyponatremia among the 
institutionalized elderly in two long-term care facilities in Taipei. J Chin Med Assoc. 
2006;69(3):115-9.
9
Huda MSB, Boyd A, Skagen K, Wile D, Van Heyningen C, Watson I, et al. 
Investigation and management of severe hyponatraemia in a hospital setting. Postgrad 
Med J. 2006;82:216-9.
10 Wald R, Jaber BL, Price LL, Updahyay A, Madias N. Impact of hospital-associated 
hyponatremia on selected outcomes. Arch Int Med. 2010;170(3):294-302.
11 Androgue JA, Madias NE. Hyponatremia. N Engl J Med. 2000;342:1581-9.
12 Hasegawa H, Okubo S, Ikezumi Y, Uchiyama K, Hirokawa T, Hirano H, et al. 
Hyponatremia due to an excess of arginine vasopressin is common in children with 
febrile disease. Pediatr Nephrol. 2009;24(3):507-11.
13 Otsuka Pharmaceutical Development & Commercialization, Inc. OPC-41061 
Investigator’s Brochure. Edition 21, Otsuka Report, issued 25 Aug 2015.
14
 An open-label, randomized, three-period crossover study of the 
pharmacokinetics and pharmacodynamics of oral tolvaptan tablets under fasting and 
non-fasting conditions in subjects of Caucasian and Japanese descent. Otsuka Clinical 
Study Report for Protocol 156-03-242, issued 23 Jul 2004.
15
 An open-label, randomized, crossover study of the effect of food 
(standard FDA high-fat breakfast) on tolvaptan pharmacokinetics in normal subjects 
following administration of 60-mg oral tolvaptan tablets. Otsuka Clinical Study 
Report for Study 156-05-256, issued 24 Jul 2006.
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16 U.S. Food and Drug Administration. Guidance for Industry. Pediatric Study Plans: 
Content of and Process for Submitting Initial Pediatric Study Plans and Amended 
Pediatric Study Plans [report on the internet]. 2013 Jul [cited 05 Jul 2013].
17 US Department of Health and Human Services: Guidance for Industry: E11 Clinical 
Investigation of Medicinal Products in the Pediatric Population. ICH December 2000.
18
  Multicenter, randomized, double-blind, placebo-controlled, efficacy and 
safety study of the effects of titrated oral tolvaptan tablets in patients with 
hyponatremia.  Otsuka Clinical Study Report for Protocol 156-02-235, issued 07 Aug 
2006.
19
 International, multicenter, randomized, double-blind, placebo-controlled, 
efficacy and safety study of the effects of titrated oral tolvaptan tablets in patients 
with hyponatremia.  Otsuka Clinical Study Report for Protocol 156-03-238, issued 25 
Jul 2006.
20 National Center for Health Statistics, National Center for Chronic Disease Prevention 
and Health Promotion. Clinical Growth Charts. Last updated Nov 2000. Available 
from: http://www.cdc.gov/growthcharts Accessed Oct 1, 2010.
21 Moritz ML, Ayus JC. Preventing neurological complications from dysnatremias in 
children. Pediatr Nephrol. 2005;20:1687-700.
22 Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia 
treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11 
Suppl 1):S1-21. 
23 Karp BI, Laureno R. Pontine and extrapontine myelinolysis; a neurologic disorder 
following rapid correction of hyponatremia. Medicine. 1993;72:359-73.
24 International Conference on Harmonisation (ICH) [homepage on the Internet]. E6: 
Good Clinical Practice: Consolidated Guideline [finalized 1996 May, corrected 1996 
Jun 1996; cited 2005 Dec 6].
25 U.S. Food and Drug Administration. Guidance for Industry. Drug-induced liver 
injury: premarketing clinical evaluation [report on the internet]. 2009 Jul [cited 15 
Feb 2014].
26 U.S. Food and Drug Administration. [available on the internet, last updated 22 Jan
2014; cited 14 Feb 2014].
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Appendix 1
Names of Sponsor Personnel
Report Immediately Reportable Events (serious adverse events, potential drug-induced 
liver injuries, and pregnancies as follows:
Country
INC Research Safety Fax Numbers
Belgium
Canada 
 (primary) or 
 (alternative)
Czech Republic
Germany
Italy
Poland
Romania
Spain
Turkey
No toll free number available;  please dial 
 (primary) or 
 (alternative)
United Kingdom
United States
 (primary) or 
 (alternative)
Project Leader/Medical Director:
Phone 
 Fax 
Clinical Management:
Phone: 
 Fax: 
Phone 
 Fax 
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Appendix 2
Institutions Concerned With the Trial
Institutions concerned with this trial are:
Sponsor
Otsuka Pharmaceutical Development &
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, USA
Phone:  
Medical Monitoring
INC Research
3201 Beechleaf Court, Suite 600
Raleigh, North Carolina 27604-1547, USA
Phone:  
Fax:  
Medical Monitor:
3210 Beechleaf Ct., Suite 600
Raleigh, North Carolina 27604, USA
Phone 
 Mobile 
Fax:  
E-Mail:
Trial Management & Clinical 
Monitoring
INC Research
3201 Beechleaf Court, Suite 600
Raleigh, North Carolina 27604-1547, USA
Phone:  
Investigational Materials
Almac Clinical Services Limited
Seagoe Industrial Estate
9 Charlestown Road
Craigavon
County Armagh
BT63 5PW
United Kingdom
Phone:
Fax:
Electronic Data Capture
MediData Solutions
79 Fifth Avenue, 8th Floor
New York, New York 10003, USA
Phone:  
Fax:  
IRT Systems (treatment assignment)
S-CLINICA
1500 Market Street
12th Floor East Tower
Philadelphia, Pennsylvania 19102, USA
Phone:  
Study Communications & Patient/Site
Support
Matthews Media Group 
700 King Farm Boulevard, Suite 500
Rockville, MD 20850, USA
Phone: 
Clinical Laboratory Supplies
Covance Central Laboratory Services
8211 SciCor Drive
Indianapolis, Indiana 46214, USA
Phone:  
Central Laboratory (PK)
ICON Development Solutions, Inc.
8282 Halsey Road
Whitesboro, New York 13492, USA
Phone:  
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IDMC Support
Chiltern (formerly Theorem Clinical 
Research)
1016 West Ninth Avenue
King of Prussia, PA, 19406, USA
Phone:  
Fax:  
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Appendix 3
Handling and Shipment of Bioanalytical Samples
All tubes must be labeled using the central laboratory’s bar code labels provided with the 
sample collection kits. The central laboratory’s requisition form must be completely 
filled out in regards to all the sample information.  In addition, the subject ID number and 
date of collection must be hand-written on the sample tube. It is important to note the 
exact time of the blood collection on the eCRF.
Each specimen must be labeled using a waterproof pen. A label suitable for the storage 
conditions must contain the subject ID number and date of collection, must correspond to 
the requisition form, and must be firmly attached. The requisition form must contain the 
name, address, and telephone number of the contact person from the trial site.
Plasma Samples for Tolvaptan
Blood (1 mL) will be collected into plastic Vacutainer tubes containing lithium heparin 
anticoagulant.  The tubes should be gently inverted 3 to 4 times and then centrifuged at 
2,000 to 3,000 rpm for at least 10 to 15 minutes at 4C.  The rpm should be kept at a 
constant setting throughout the trial.  Plasma should be stored at −20C or on dry ice.  
Samples should be shipped monthly.
Shipment of Plasma
Plasma samples must be neatly packed in the kits provided by the central laboratory and 
restrained in a Styrofoam container that is completely filled with dry ice to avoid air 
spaces that allow evaporation of the dry ice.  The Styrofoam container should be sealed 
with tape and placed in a cardboard box.  The central laboratory must be alerted of 
sample shipment.  Packages must not be shipped on Thursday, Fridays, Saturdays, or any 
day prior to a holiday without the expressed consent of OPDC or the central laboratory. 
Shipments from clinical trial sites will be via an overnight carrier to the central laboratory 
(Clinical Laboratory Supplies, Covance Central).


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Appendix 4
Tanner Staging
Classification of Sex Maturity Stages in Girls
Stage
Pubic Hair
Breasts
1
Preadolescent
Preadolescent
2
Sparse, lightly pigmented, straight, medial 
border of labia
Breast and papilla elevated as small mound; 
areolar diameter increased
3
Darker, beginning to curl, increased amount
Breast and areola enlarged, no contour 
separation
4
Coarse, curly, abundant but amount less than 
adult
Areola and papilla form secondary mound
5
Adult feminine triangle, spread to medial 
surface of thighs
Mature; nipple projects, areola part of the 
general breast contour
Classification of Sex Maturity Stages in Boys
Stage
Pubic Hair
Penis
Testes
1
Preadolescent
Preadolescent
Preadolescent
2
Scanty, long, slightly 
pigmented
Slight enlargement
Enlarged scrotum, pink 
texture altered
3
Darker, starts to curl, small 
amount
Longer
Larger
4
Resembles adult type but less 
in quantity; coarse, curly
Larger; glans and breadth 
increase in size
Larger, scrotum dark
5
Adult distribution, spread to 
medial surface of thighs
Adult size
Adult size


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Appendix 5
Optional Tolvaptan Treatment Component: Eligibility
Criteria
Subjects will be eligible for tolvaptan treatment if they meet the criteria outlined in the 
table below.
Eligibility Criteria for Optional Tolvaptan Treatment
1.
Male or female subjects ≥4 years of age (or per local Health Authority age restrictions) and ≥ 10 kg
2.
The subject must have been off treatment with the investigational medicinal product (IMP) for at 
least 7 days following the end of treatment in the previous tolvaptan trial for hyponatremia 
(euvolemic or hypervolemic)
3.
Persistent dilutional (euvolemic or hypervolemic) hyponatremia defined as being documented as 
present for at least 48 hours, evidenced by at least 2 serum sodium assessments < 130 mEq/L 
(mmol/L) drawn at least 12 hours apart (these values can be documented using historical values 
previously obtained per standard of care); a third (STAT) serum sodium assessment < 130 mEq/L 
(mmol/L), which will serve as the baseline value for efficacy endpoints, is to be obtained within 
2 to 4 hours prior to the first dose of tolvaptan
4.
Ability to swallow tablets
5.
Ability to maintain adequate fluid intake whether orally or via IV support with adequate monitoring
6.
Ability to comply with all requirements of the trial
7.
Trial-specific written informed consent/assent obtained from a parent/guardian or legally acceptable 
representative, as applicable per age of subject or local laws, prior to the initiation of any protocol-
required procedures.  In addition, the subject as required by local laws must provide informed assent 
at the pretreatment baseline for this trial and must be able to understand that he or she can withdraw 
from the trial at any time.  All informed consent/assent procedures must be in accordance with the 
trial center’s IRB/IEC and local regulatory requirements
8.
Ability to commit to remain fully abstinent (periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods] or withdrawal are not acceptable methods of contraception)
or practice double-barrier birth control during the trial and for 30 days following the last dose of 
tolvaptan for sexually active females of childbearing potential
Subjects will be ineligible for tolvaptan treatment if they meet any of the following 
criteria:
Ineligibility Criteria for Tolvaptan Treatment
1.
Has evidence of hypovolemia or intravascular volume depletion (eg, hypotension, clinical evidence 
of volume depletion, response to saline challenge); if the subject has systolic blood pressure or heart 
rate outside of the normal range for that age volume status should be specifically clinically assessed 
to rule out volume depletion.
2.
Has serum sodium < 120 mEq/L (mmol/L), with or without associated neurologic impairment (ie, 
symptoms such as apathy, confusion, or seizures)
3.
Use of potent CYP3A4 inhibitors in subjects 50 kg or moderate CYP3A4 inhibitors in subjects 
< 20 kg
4.
Lacks free access to water (inability to respond to thirst) or without ICU-level fluid monitoring and 
management
5.
Has a history or current diagnosis of nephrotic syndrome
6.
Has transient hyponatremia likely to resolve (eg, head trauma or post-operative state)
7.
Has hyperkalemia defined as serum potassium above the ULN for the appropriate pediatric age 
range


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Ineligibility Criteria for Tolvaptan Treatment
8.
Has eGFR < 30 mL/min/1.73 m2 calculated by the following equation:
eGFR (mL/min/1.73 m2) = 0.413 height (cm)/serum creatinine (mg/dL)
9.
Has acute kidney injury defined as:

Increase in serum creatinine by 0.3 mg/dL (26.5 mol/L) within 48 hours; or

Increase in serum creatinine to 1.5 times baseline, which is known or presumed to have 
occurred within the prior 7 days; or

Urine volume < 0.5 mL/kg/h for 6 hours
10.
Has severe or acute neurological symptoms requiring other intervention (eg, hyperemesis, 
obtundation, seizures)
11.
Has had treatment for hyponatremia with:

Hypertonic saline (including normal saline challenge) within 8 hours of qualifying serum 
sodium assessments;

Urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of qualifying serum 
sodium assessments;

Other treatment for the purpose of increasing serum sodium concurrent with dosing of trial 
medication
12.
Has anuria or urinary outflow obstruction, unless the subject is, or can be, catheterized during the 
trial
13.
Has a history of drug or medication abuse within 3 months prior to the pretreatment visit or current 
alcohol abuse
14.
Has a history of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine 
derivatives (such as benazepril)
15.
Has psychogenic polydipsia (subjects with other psychiatric illness may be included per medical 
monitor approval)
16.
Has uncontrolled diabetes mellitus, defined as fasting glucose > 300 mg/dL (16.7 mEq/L [mmol/L])
17.
Has screening liver function values > 3 ULN. 
18.
Patient who has cirrhosis and meets any of the following conditions: a major GI bleed within the 
past 6 months, evidence of active bleeding (eg, epistaxis, petechiae/purpura, hematuria, or 
hematochezia), platelet count < 50,000/L, or use of concomitant medications known to increase 
bleeding risk
19.
Has hyponatremia due to the result of any medication that can safely be withdrawn (eg, thiazide 
diuretics)
20.
Has hyponatremia (eg, hyponatremia in the setting of adrenal insufficiency, untreated 
hypothyroidism, or hypotonic fluid administration) that is most appropriately corrected by 
alternative therapies
21.
Is currently pregnant or breastfeeding
22.
Has any medical condition that, in the opinion of the investigator, could interfere with evaluation of 
the trial objectives or safety of the subjects
23.
Is deemed unsuitable for trial participation in the opinion of the investigator
24.
Participation in an investigational drug trial (other than a previous tolvaptan hyponatremia trial) 
within the past 30 days, without prior approval from the medical monitor
25.
Subjects < 4 years of age (or per local Health Authority age restrictions), weight < 10 kg, or who are 
unable to swallow tablets
AKI = acute kidney injury; eGFR = estimated glomerular filtration rate; GI = gastrointestinal; 
ICU = intensive care unit; IRE = Immediately Reportable Event; ULN = upper limit of normal


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Appendix 6
Optional Tolvaptan Treatment Component: Laboratory 
Assessment Schedule
Frequency of Recurring Laboratory Assessments
Treatment Phase
Serum Sodium
LFTs 
(ALT, AST, BT) 
and creatinine
PKa
Pretreatment Baseline 
doses
Day -1 to Day -4: 
assessments 130 mEqL 
(mmol/L) 12 hours apart
Required at 
baseline if not done 
within the previous 
month
Month 1: Titrationb
Once daily efficacy 
assessment and additional  
safety assessments 4 to 6 
hours and 18 hours postdose
Month 1: Post-titrationc 
Once weekly 
Once monthly
Month 2: Post-titration 
(steady dose)
Every 2 weeks
Once monthly
Once post 8 weeks 
of continuous 
treatment
Month 3+ post-titration 
(steady dose): 
Maintenance (Months 3, 
4, and 5)
Once monthly
Once monthlyd,e
Month 6 
24 (4) hours postdose
Once
Post-last dose Follow-up 
each cycle
24 (4) hours and 7 (1) 
days
aOnce post 8 weeks for every new cycle of treatment
bDay 1 up to Day 4
cDays 7, 14, and 21
dAST, ALT, and BT will be assessed if more than 1 month has elapsed since LFTs were performed
eSee Section 3.7.5.3.1 for more information and Section 5.4 for detailed instructions on follow-up of 
subjects with elevations in AST, ALT, or BT that are 2 ULN or levels that increase 2 x from 
baseline.
NA = Not applicable.


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Appendix 7
Protocol Amendments
Amendment Number:
1
Issue Date:
5 Sep 2014
PURPOSE:

To increase the consistency of this protocol with other tolvaptan pediatric 
hyponatremia protocols

To revise trial endpoints in accordance with the Pediatric Investigation 
Plan

To clarify study design, procedures, and assessments

To incorporate revised definitions of IMP causality
BACKGROUND:
As several protocols in the tolvaptan hyponatremia pediatric development program were 
being conceived through negotiations with both US and European regulatory agencies, it 
became apparent that they needed to be aligned more closely in order to achieve more
consistency in data collection and to allow for data to be generated that could be 
synthesized and analyzed across trials. This protocol amendment also aligns the trial 
endpoints with the Pediatric Investigation Plan.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
MODIFICATIONS TO PROTOCOL:
Sectional Revisions:  changes made to specific sections of the protocol are listed in the 
table below.


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Title Page
Clinical Management
Issue Date:
31 Oct 2013
Clinical Management
Issue Date:
31 October 2013
Date of Amendment 1:
5 September 2014
Synopsis -
Clinical 
Phase/Trial Type
Phase 3b, safety follow-up with optional open-label extension
Phase 3b, safety follow-up with optional open-label tolvaptan 
treatment component
Synopsis -
Treatment 
Indication
Euvolemic or hypervolemic hyponatremia
Dilutional (euvolemic or hypervolemic) hyponatremia
Synopsis -
Objectives
For all subjects:

To evaluate the post-treatment safety follow-up of children 
and adolescent subjects with euvolemic or hypervolemic 
hyponatremia who have previously participated in a trial of 
titrated oral tolvaptan
For subjects who receive tolvaptan:

To demonstrate that tolvaptan safely and effectively 
achieves and maintains increased serum sodium 
concentrations in children and adolescent subjects with 
euvolemic or hypervolemic hyponatremia when used for 
both multiple short-term treatments and/or longer chronic 
treatments
This trial will consist of a core safety follow-up component 
(duration:  6 months) and an optional tolvaptan treatment 
component (duration:  variable, depending on the subjects’ 
continuing need for tolvaptan treatment). 
The objectives of this trial are:
Core Safety Follow-up Component

For all subjects:  To evaluate the post-treatment safety 
follow-up of children and adolescent subjects with 
dilutional (euvolemic or hypervolemic) hyponatremia who 
have previously participated in a trial of titrated oral 
investigational medicinal product (IMP [tolvaptan in Trial 
156 08 276, tolvaptan or placebo in Trials 156-13-207 and 
156-12-205]).
Optional Tolvaptan Treatment Component

For subjects who receive tolvaptan:  To demonstrate that 
tolvaptan safely and effectively achieves and maintains 
increased serum sodium concentrations in children and 
adolescent subjects with dilutional (euvolemic or 
hypervolemic) hyponatremia when used for both multiple 
short-term treatments and/or longer chronic treatments.
Synopsis - Trial 
Design
This is an observational, follow-up trial in children and adolescents 
who have previously participated in a trial of titrated oral tolvaptan 
Core Safety Follow-up Component
This is a 6-month safety follow-up trial in children and adolescents 
PPD
PPD
PPD
PPD


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for euvolemic or hypervolemic hyponatremia.  Subjects who were 
enrolled in one of the tolvaptan pediatric efficacy, safety, 
pharmacokinetic (PK), and pharmacodynamic trials for 
hyponatremia (ie, Trials 156-08-276, 156-12-205, or 156-13-207) 
are eligible for participation in this trial.
Enrollment in this trial should directly follow completion or 
discontinuation of the previous trial.  The end of trial visit in the 
previous trial will serve as the Baseline Visit in this trial.  Subjects 
will be followed once a month for 6 months, alternating between 
telephone contact and in-clinic visits, to clinically evaluate children 
and adolescent subjects with hyponatremia, regardless of the need 
for treatment.  If a subject has a clinical need for treatment with 
tolvaptan, the subject may be screened for eligibility to be dosed 
with tolvaptan.  The subject must have been off of treatment with 
the investigational medicinal product (IMP) for a minimum of 7 
days following the end of treatment in the previous trial to assess the 
subject’s clinical need for dosing.  Subjects can be treated with 
tolvaptan during and/or after the initial 6-month follow-up period.
Since hyponatremia in this patient population can often be transient 
and/or may be secondary to hypovolemic states, subjects will be 
screened for hyponatremic histories as well as clinically evaluated 
to rule out such cases before being dosed with tolvaptan.  For the 
purpose of determining eligibility for treatment with tolvaptan 
within this protocol, persistent hyponatremia will be defined as 
serum sodium assessments < 130 mmol/L documented as present 
for at least 48 hours.  Specifically, subjects must have at least 2 
documented serum sodium assessments < 130 mmol/L drawn at 
least 12 hours apart.  These values can be documented using 
historical values previously obtained as per standard of care.  A 
third (immediate) serum sodium assessment < 130 mmol/L, which 
will serve as the baseline value for efficacy endpoints, is to be 
obtained within 3 (1) hours of the first dose of trial medication.  
Additional qualification assessments will be performed as per 
etiology of hyponatremia.  The first dose of trial medication will be 
who have previously participated in a trial of titrated IMP (tolvaptan 
in Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 
156-12-205) for dilutional (euvolemic or hypervolemic) 
hyponatremia.  
Enrollment in this trial should directly follow completion or 
discontinuation of the previous trial of titrated oral IMP (tolvaptan 
in Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 
156-12-205).
Subjects who consent/assent to participate will be followed once a 
month for 6 months, alternating between telephone calls and clinical 
trial site visits, to clinically evaluate children and adolescent 
subjects with dilutional (euvolemic or hypervolemic) hyponatremia, 
regardless of the need for treatment.
Optional Tolvaptan Treatment Component
Any subject enrolled in the core safety follow-up component who 
has a medical need for tolvaptan per the investigator’s assessment, 
may have short-term treatment (ie, a few days of treatment needed 
per episode of hyponatremia) or long-term treatment (ie, treatment 
for weeks to months with concomitant medication). The need for 
treatment beyond 30 days will be determined by a scheduled 
treatment discontinuation.
The subject must have been off treatment with the IMP (tolvaptan in 
Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 
156-12-205) for 7 days following the end of treatment in the 
previous trial of titrated oral IMP to assess the subject’s clinical 
need for dosing.  Subjects can be treated with tolvaptan during 
and/or after the 6-month follow-up period (core safety follow-up 
component).
Treatment can be discontinued and reinitiated depending upon the 
individual subject’s need (eg, during chemotherapy treatments).  If 
subjects are off tolvaptan treatment for >72 hours, reinitiation of 


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administered upon successful completion of all pretreatment 
baseline procedures.
Eligible subjects will initially be administered tolvaptan once daily 
and subsequently titrated in a hospital setting.  Follow-up may occur 
in the hospital if the subject has not been discharged or the subject 
may return for outpatient visits if the subject has been discharged 
from the hospital.
Treatment with tolvaptan can continue per clinical need as 
determined by the investigator in consultation with the sponsor’s 
medical monitor.  The treatment should be tailored to the needs of 
an individual subject.  Serum sodium concentrations will be 
assessed during the treatment cycle and at 48 (4) hours and 7 (+ 1) 
days post-last dose.  Up-titration of tolvaptan doses can occur once
daily and will be based on serum sodium levels at > 20 hours 
following initiation of therapy and each subsequent dose; up-
titration may not occur within 20 hours of the previous dose.
Treatment can be discontinued and reinitiated as needed per 
individual subject’s need (eg, during chemotherapy treatments).  If 
subjects are off of tolvaptan treatment for 48 hours, reinitiation of 
treatment will require reassessment of the eligibility criteria and 
should begin in a hospital setting.  Tolvaptan should be titrated with 
regular serum sodium assessments.  After discontinuation of trial 
medication, serum sodium should be assessed at 48 (4) hours and 
7 (+ 1) days post-last dose.
treatment will require reassessment of the eligibility criteria and will 
begin in a hospital setting.  Tolvaptan should be titrated with regular 
serum sodium assessments.
Synopsis -
Subject 
Population
Up to 140 male and female subjects may be eligible for this trial; 
subjects will need to have completed at least one of the previous 
tolvaptan pediatric trials for hyponatremia (ie, Trials 156-08-276, 
156-12-205, or 156-13-207).
Subjects with euvolemic or hypervolemic hyponatremia eligible to 
be screened for treatment with tolvaptan include, but are not limited 
to, those diagnosed and admitted to a hospital for treatment of heart 
failure, hepatocellular disease (including cirrhosis), or syndrome of 
Up to 140 male or female subjects may be eligible for this trial; 
subjects will need to have participated in one of the previous 
tolvaptan pediatric trials for dilutional (euvolemic or hypervolemic) 
hyponatremia (ie, Trials 156-08-276, 156-13-207, or 156-12-205).


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inappropriate secretion of antidiuretic hormone (SIADH).  Subjects 
with acute hyponatremia or hyponatremia expected to resolve 
spontaneously will be ineligible for tolvaptan treatment.  Children 
with an impaired ability to sense or communicate their thirst will 
either be required per protocol to undergo closer in-hospital 
observation, laboratory and urine output monitoring, or will be 
ineligible for tolvaptan treatment if this is not possible.
The eligibility criteria for tolvaptan treatment have been designed to 
ensure careful selection of subjects with chronic (48 hours) 
dilutional hyponatremia (euvolemic or hypervolemic) associated 
with heart failure, hepatocellular disease (including cirrhosis), or 
SIADH who may benefit from treatment with tolvaptan, while 
excluding those who have acute or transient hyponatremia, have 
overt symptoms of hyponatremia requiring immediate intervention, 
or who are at increased risk for developing hyponatremic 
encephalopathy or osmotic demyelination.
Synopsis -
Inclusion/ 
Exclusion 
Criteria
Key inclusion criteria:

Enrollment in at least one of the previous tolvaptan 
pediatric trials for hyponatremia (ie, Trials 156-08-276, 
156-12-205, or 156-13-207)

Willing to be clinically followed for 6 months
Exclusion criteria:
There are no exclusion criteria for entry into this trial.
Key inclusion criteria:

Participation in one of the previous tolvaptan pediatric 
trials for hyponatremia (ie, Trials 156-08-276, 156-13-207, 
or 156-12-205).

Willingness to be clinically followed for 6 months.
Exclusion criteria:

There are no exclusion criteria for entry into the core safety 
follow-up component of this trial.
Synopsis - Trial 
Sites
Subjects may be enrolled at up to 65 centers globally.
Subjects may be enrolled at up to 65 clinical trial sites globally.
Synopsis -
Investigational 
Medicinal 
Product, Dose, 
Formulation, 
Mode of 
Subjects enrolled in this trial will not receive IMP unless they 
demonstrate a clinical need as determined by the investigator and 
meet the eligibility criteria for treatment.
Tolvaptan will initially be supplied as 3.75-, 7.5-, 15-, and 30-mg 
spray-dried tablets.  Upon the availability of a liquid formulation, 
Subjects enrolled in this trial will not receive tolvaptan unless they 
demonstrate a clinical need as determined by the investigator and 
meet the eligibility criteria for treatment.
Tolvaptan will initially be supplied as 3.75-, 7.5-, 15-, and 30-mg 
spray-dried tablets.  Upon the availability of an oral liquid 


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Administration
the protocol will be amended to reflect additional dosing options.
Tolvaptan will be administered once daily orally with a dose 
proportional amount of water.  Doses of 15 mg tolvaptan will be 
given with 240 mL of water, 7.5 mg tolvaptan will be given with 
120 mL of water, and 3.75 mg tolvaptan will be given with 60 mL 
of water.  The duration of administration of tolvaptan will be per 
medical need as determined by the principal investigator.  Eligible 
subjects may have short-term treatment (ie, a few days of treatment 
needed per episode of hyponatremia) or long-term treatment (ie, 
treatment for weeks to months with concomitant medication).
Subjects will be administered tolvaptan on an age- and weight-based 
scale.  Up-titration of tolvaptan doses will be based on serum 
sodium levels at > 20 hours following initiation of therapy; a change 
in serum sodium 4 mmol/L from baseline should warrant 
up-titration, which is limited to no more than twice the previous 
dose.

Subjects < 2 years of age or weighing < 10 kg will be 
excluded until the availability of a liquid formulation. 
Tolvaptan metabolism is primarily mediated by 
cytochrome P450 (CYP) 3A4 and intestinal and hepatic 
concentrations of this enzyme increase following birth.  
Developmental information from PK models of midazolam 
and cisapride, other CYP3A4 substrates, in neonates and 
infants will be used to provide dosing recommendations for 
the liquid formulation when available.

Subjects 2 years of age and weighing 10 to < 20 kg will 
be given a 3.75-mg tablet on Day 1 with possible 
up-titration to 7.5- and 15-mg doses.

Subjects weighing 20 to 50 kg, inclusive, will be given a 
7.5-mg tablet on Day 1 with possible up-titration to 15- and 
30-mg doses.

Subjects weighing > 50 kg will be given a 15-mg tablet on 
formulation, the protocol will be amended to reflect additional 
dosing options.
Tolvaptan tablets will be administered orally once daily (QD), 
preferably in the morning hours, with a dose-proportional amount of 
water.  Doses of 15 mg tolvaptan will be given with 240 mL of 
water, 7.5 mg of tolvaptan will be given with 120 mL of water, and 
3.75 mg of tolvaptan will be given with 60 mL of water.  Any 
initiation or titration of tolvaptan must occur in a hospital setting.
If a subject is not expected to receive a higher dose of tolvaptan, ie, 
if a stable dose is determined, continued administration can be done 
outside of the hospital setting.  Subjects can be treated with 
tolvaptan during and/or after the 6-month core safety follow-up 
component.


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Day 1 with possible up-titration to 30- and 60-mg doses.
The subjects will continue dosing according to a titration scheme 
targeting a final sodium concentration between 135 and 
140 mmol/L.  Titration will ideally achieve a change in serum 
sodium concentration of at least 4 to 8 mmol/L/24 hours but not 
12 mmol/L/24 hours.
Subjects will receive daily doses of oral tolvaptan based on 
individual titration results and clinical need.  Treatment can 
continue or be discontinued and reinitiated per clinical need as 
determined by the investigator in consultation with the sponsor’s 
medical monitor.  Reinitiation of treatment after a subject is off of 
tolvaptan for 48 hours will require reassessment of the eligibility 
criteria.
Subjects will be required to be in a hospital setting during initiation 
or up-titration of tolvaptan.  If a subject is not expected to receive a 
higher dose of tolvaptan, continued administration can be done 
outside of the hospital setting.
Synopsis - Trial 
Assessments
Safety:

Adverse event reporting

Vital signs

Clinical laboratory tests

Physical examinations

Body height and weight

Tanner Staging
Efficacy for tolvaptan treatment:

Serum sodium concentration
Pharmacokinetics for tolvaptan treatment:

Sparse blood samples for tolvaptan and plasma metabolite 
concentrations from subjects dosed with tolvaptan for 
8 consecutive weeks (one assessment per initiation or 
Safety:

Vital signs

Physical examinations

Body height and weight/Growth percentiles

Tanner Staging

Clinical laboratory tests: Serum sodium assessments and 
liver function tests (alanine transaminase [ALT], aspartate 
aminotransferase [AST], and total bilirubin [BT])

Adverse event reporting
Efficacy for tolvaptan treatment:

Serum sodium concentration

Continued need for tolvaptan treatment after the first 
30 days of treatment.


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reinitiation of therapy at 8 weeks)
Baseline:

Medical and hyponatremia history

Urine pregnancy tests (subjects eligible for tolvaptan 
treatment only)

Clinical laboratory tests
Pharmacokinetics for tolvaptan treatment:
Sparse blood samples for tolvaptan and plasma metabolite 
concentrations from subjects dosed with tolvaptan for 8 consecutive 
weeks (one assessment per initiation or reinitiation of therapy at 
8 weeks).
Synopsis -
Criteria for 
Evaluation
Primary Endpoints:
Safety:

Adverse events, including cases of dehydration

Vital signs

Body weight, height, and growth percentiles

Tanner Stages
Safety for tolvaptan treatment:
In addition to the safety variables reported for all subjects, the 
following variables will be assessed for subjects on tolvaptan:

Percentage of subjects with overly rapid improvement in 
serum sodium (12 mmol/L in 24 hours after the first dose 
at introduction or reintroduction of IMP)

Percentage of subjects who experience recurrence of 
hyponatremia while on IMP

Clinical laboratory abnormalities:

Serum sodium, overly rapid changes in serum sodium

Changes from baseline in alanine transaminase and 
aspartate transaminase
Secondary Endpoints:
Efficacy for tolvaptan treatment:

Change in serum sodium from baseline at each visit while 
the IMP is being administered.  Serum sodium will be 
assessed daily during titration.  Then, it will be assessed at 
each visit, at a minimum monthly once a subject has 
reached the optimal dose.
Primary Endpoint:

Change from baseline in serum sodium while tolvaptan is 
being administered 
Secondary Endpoints:
Efficacy:

Percentage of subjects who require rescue therapy while on 
tolvaptan treatment

Percentage of subjects requiring continuation of tolvaptan 
following 30 days of treatment

Change from baseline in QoL assessments for all subjects
Safety:

Percentage of subjects with overly rapid correction in 
serum sodium (12 mEq/L [mmol/L]) in 24 hours after the 
first dose at introduction or reintroduction of tolvaptan)

Changes from baseline in ALT, AST, and BT for subjects 
on tolvaptan

Frequency of AE reports for all subjects

Changes from baseline in growth percentiles (weight and 
height) for all subjects

Tanner Staging progression for all subjects
Pharmacokinetics for tolvaptan treatment:

Plasma concentrations of tolvaptan and metabolites in 
subjects who have continued tolvaptan therapy for 
8 consecutive weeks.


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Pharmacokinetics for tolvaptan treatment:

Plasma concentrations of tolvaptan and metabolites in 
subjects who have continued tolvaptan therapy for 
8 consecutive weeks
Exploratory Endpoint:
Safety:

Quality of Life assessments
Synopsis -
Statistical 
Methods
The primary and secondary analyses will use descriptive statistics.
Primary and secondary endpoints will be summarized by descriptive 
statistics. A paired Student’s t-test will be used to evaluate growth 
data, eg, height, body weight, and growth percentiles.  Tanner 
Staging will be analyzed using the Cochran-Mantel-Haenszel row 
mean scores differ test controlling for subjects.
Synopsis - Trial 
Duration
The trial duration is expected to continue until tolvaptan becomes 
approved for the pediatric population.  All enrolled subjects will be 
followed for a minimum of 6 months.  For subjects on active 
treatment with tolvaptan, the length of participation for each 
individual subject will vary depending on the duration of treatment 
required and if repeat treatments are necessary.
The core safety follow-up component of the trial is expected to 
continue until all enrolled subjects from Trials 156-08-276, 
156-13-207, or 156-12-205 have been followed for a minimum of 
6 months.  For subjects in the optional tolvaptan treatment 
component, the length of participation for each individual subject 
will vary depending on duration of treatment required and the need 
for repeated treatments.  The opportunity to participate in the 
Optional Tolvaptan Treatment Component is planned to remain 
open until the last subject completes the Core Safety Follow-up 
Component.
List of 
Abbreviations
Abbreviations removed: 
CRF
Case report form
FENa
Fractional excretion of sodium
FE urate
Fractional excretion of urate
Abbreviations added:
BT
Total bilirubin
cAMP
Cyclic adenosine monophosphate
CKD
Chronic kidney disease
CrCL
Creatinine clearance
eCRF
Electronic case report form
EMA
European Medicines Agency
MHLW
Ministry of Health, Labour, and Welfare (Japan)
NA
Not applicable
NOAEL
No observed adverse effects level
QD
Once daily


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QoL
Quality of Life
SALT
Study of Ascending Levels of Tolvaptan in 
Hyponatremia
SALTWATER
Safety and sodium Assessment of Long-term 
Tolvaptan With hyponatremia:  A year-long, 
open-label Trial to gain Experience under Real-
world conditions
Section 1 
Introduction
Sodium is the major extracellular electrolyte and is a key factor in 
maintaining extracellular osmolality and transmembrane electrical 
and chemical potentials.  Serum sodium concentration is maintained 
within a narrow range (normally 135 to 145 mmol/L) to facilitate 
optimal cellular hydration and neuromuscular function.  Sodium 
concentration is normally balanced through integrated actions of the 
cardiovascular, renal, endocrine, gastrointestinal (GI), and nervous 
systems.
Hyponatremia is a disease seen in all age groups, including 
pediatrics, and across a wide range of patients “from asymptomatic 
to the critically ill.”  It is characterized by a subnormal 
concentration of sodium in the blood (serum sodium < 135 mmol/L) 
and is manifest by a range of neurological symptoms which, left 
untreated, can lead to seizure, obtundation, hypoxia, and death.  
Hyponatremia is rarely seen in isolation and typically is found in 
association with disorders, behaviors, or circumstances which 
promote an imbalance of fluid/sodium homeostasis.  Children, in 
particular those hospitalized and receiving parenteral fluids (eg, 
post-operative maintenance and hydration with hypotonic fluid), are 
at risk for developing hyponatremia.
Both forms of hyponatremia, dilutional and depletional, impair 
normal neurological function and therefore represent a disease state.  
Furthermore, there is evidence suggesting that, in both children and 
adults, hyponatremia has more serious consequences than 
previously believed.  Various clinical and nonclinical experiments 
and case studies have documented the role of sodium in maintaining 
extracellular osmolality and transmembrane electrical and chemical 
Sodium is the major extracellular electrolyte and is a key factor in 
maintaining extracellular osmolality and transmembrane electrical 
and chemical potentials.  Serum sodium concentration is maintained 
within a narrow range (normally 135 to 145 mEq/L [mmol/L]) to 
facilitate optimal cellular hydration and neuromuscular function.  
Sodium concentration is normally balanced through integrated 
actions of the cardiovascular, renal, endocrine, gastrointestinal (GI), 
and nervous systems.
Hyponatremia is a disease seen in all age groups, including 
pediatrics, and across a wide range of patients “from asymptomatic 
to the critically ill.” It is characterized by a subnormal concentration 
of sodium in the blood (serum sodium < 135 mEq/L [mmol/L]) and 
is manifested by a range of neurologic symptoms which, left 
untreated, can lead to seizure, obtundation, hypoxia, and death.  
Hyponatremia is rarely seen in isolation and typically is found in 
association with disorders, behaviors, or circumstances which 
promote an imbalance of fluid/sodium homeostasis.  Children, in 
particular those hospitalized and receiving parenteral fluids (eg, 
post-operative maintenance and hydration with hypotonic fluid), are 
at risk for developing hyponatremia.
Both forms of hyponatremia, dilutional and depletional, impair 
normal neurologic function and therefore represent a disease state.  
Furthermore, there is evidence suggesting that, in both children and 
adults, hyponatremia has more serious consequences than 
previously believed.  Various clinical and nonclinical experiments 
and case studies have documented the role of sodium in maintaining 
extracellular osmolality and transmembrane electrical and chemical 


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potentials.  Sudden decreases in the concentration of extracellular 
sodium lead to influx of water into cells, often resulting in cerebral 
edema, irreversible neurological damage, respiratory arrest, 
brainstem herniation, and death if not treated quickly and 
appropriately.  When hyponatremia persists, osmotic adjustments 
can occur over hours to days through metabolic elimination of 
electrolytes and then osmotically-active organic compounds from 
the cells.  While these compensatory mechanisms can prevent acute 
brain herniation, chronic symptoms of hyponatremia may arise from 
electrochemical imbalances in cations that are important for nerve 
conduction and/or imbalances in amino acids and neurotransmitters 
dependent on sodium for transport.  Disturbances in these 
physiological processes lead to symptoms and outcomes which 
depend on a number of factors, including rapidity of onset, severity 
of hyponatremia, persistence of underlying disease, and clinical 
context (age, gender, baseline neurological function).  In many 
cases, morbidity and mortality associated with hyponatremia can be 
shown to be prevented or reversed with appropriate and timely 
correction of serum sodium concentration.
In the adult population, hyponatremia occurs in 7% to 8% of 
elderly, ambulatory patients and 15% to 20% of hospitalized 
patients, making it the most common serum electrolyte abnormality 
that physicians encounter, and a prevalent problem for those 
hospitalized for a wide variety of critical illnesses.  A similar 
situation exists for children in which approximately 25% of 
hospitalized children were found to have mild hyponatremia (serum 
sodium < 135 mmol/L) and approximately 1% were found to have 
moderate hyponatremia (serum sodium < 130 mmol/L).
Hyponatremia is associated with significant additional hospital 
morbidity and cost.
Children, especially infants, are particularly vulnerable to sodium 
and other electrolyte imbalances due to their relatively immature 
renal function, increased insensible water loss, and their limited 
ability to communicate thirst.  Hence, hyponatremia is not 
potentials.  Sudden decreases in the concentration of extracellular 
sodium lead to influx of water into cells, often resulting in cerebral 
edema, irreversible neurologic damage, respiratory arrest, brainstem 
herniation, and death if not treated quickly and appropriately.  When 
hyponatremia persists, osmotic adjustments can occur over hours to 
days through metabolic elimination of electrolytes and then 
osmotically-active organic compounds from the cells.  While these 
compensatory mechanisms can prevent acute brain herniation, 
chronic symptoms of hyponatremia may arise from electrochemical 
imbalances in cations that are important for nerve conduction and/or 
imbalances in amino acids and neurotransmitters dependent on 
sodium for transport.  Disturbances in these physiological processes 
lead to symptoms and outcomes which depend on a number of 
factors, including rapidity of onset, severity of hyponatremia, 
persistence of underlying disease, and clinical context (age, sex, 
baseline neurologic function).  In many cases, morbidity and 
mortality associated with hyponatremia can be shown to be 
prevented or reversed with appropriate and timely correction of 
serum sodium concentration.
In the adult population, hyponatremia occurs in 7% to 8% of 
elderly, ambulatory patients6 and 15% to 20% of hospitalized 
patients,6,7,8,9 making it the most common serum electrolyte 
abnormality that physicians encounter, and a prevalent problem for 
those hospitalized for a wide variety of critical illnesses.  A similar 
situation exists for children in which approximately 25% of 
hospitalized children were found to have mild hyponatremia (serum 
sodium < 135 mEq/L [mmol/L]) and approximately 1% were found 
to have moderate hyponatremia (serum sodium < 130 mEq/L 
[mmol/L]).4  Hyponatremia is associated with significant additional 
hospital morbidity and cost.10
Children, especially infants, are particularly vulnerable to sodium 
and other electrolyte imbalances because of their relatively 
immature renal function, increased insensible water loss, and limited 
ability to communicate thirst.  Hence, hyponatremia is not 


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uncommon in hospitalized children and pediatric patients presenting 
at the Emergency Department.  Hyponatremia in children is most 
often caused by gastroenteritis and water intoxication, the former 
leading to hypovolemic volume state and requiring fluid 
administration.  Other underlying diseases that can be accompanied 
by either euvolemic or hypervolemic hyponatremia are congenital 
heart failure, liver diseases, adrenal insufficiency, and renal 
disorders.  The syndrome of inappropriate secretion of antidiuretic 
hormone (SIADH) is often associated with central nervous system 
or pulmonary conditions and also malignancies.  An excess of 
arginine vasopressin (AVP) excretion with impaired free water 
excretion can lead to hyponatremia in febrile children and 
approximately 30% of these hospitalized children have SIADH.  In 
addition, several drugs such as thiazide diuretics, antidepressants, 
anticonvulsants, and chemotherapeutics have been associated with 
SIADH.
The United States (US) Food and Drug Administration (FDA) has 
required pediatric trials be conducted for tolvaptan for the indication 
of hyponatremia.  This trial is an extension trial to follow children 
and adolescent subjects who were enrolled in a previous tolvaptan 
pediatric trial for hyponatremia.  In addition, this trial will allow 
continued access to tolvaptan to those subjects with a clinical need 
per the investigator’s discretion.
uncommon in hospitalized children and pediatric patients presenting 
at the Emergency Department.  Hyponatremia in children is most 
often caused by gastroenteritis and water intoxication, the former 
leading to hypovolemic volume state and requiring fluid 
administration.  Other underlying diseases that can be accompanied 
by dilutional (euvolemic or hypervolemic) hyponatremia are 
congenital heart failure, liver diseases, adrenal insufficiency, and 
renal disorders.  The syndrome of inappropriate secretion of 
antidiuretic hormone (SIADH) is often associated with central 
nervous system or pulmonary conditions and also malignancies.  An 
excess of arginine vasopressin (AVP) excretion with impaired free 
water excretion can lead to hyponatremia in febrile children and 
approximately 30% of these hospitalized children have SIADH.  In 
addition, several drugs such as thiazide diuretics, antidepressants, 
anticonvulsants, and chemotherapeutics have been associated with 
SIADH.
The United States (US) Food and Drug Administration (FDA) and 
the European Medicines Agency (EMA) have required that pediatric 
trials be conducted for tolvaptan for the indication of hyponatremia.  
This trial is an extension trial to follow children and adolescent 
subjects who participated in a previous tolvaptan pediatric trial for 
hyponatremia.  In addition, this trial will allow continued access to 
tolvaptan to those subjects with a clinical need per the investigator’s 
discretion.
Section 1.2 
Clinical Data
Tolvaptan was approved in adults by the US FDA, the European 
Union, and 9 other countries for the treatment of specific forms of 
hyponatremia and by the Japanese Ministry of Health, Labour, and 
Welfare for volume overload in heart failure.  Tolvaptan is currently 
being developed for the treatment of autosomal dominant polycystic 
kidney disease (ADPKD), and for the treatment of hepatic edema 
and carcinomatous edema.  As of 31 Mar 2013, 83 trials have been 
completed, 2 trials were terminated due to slow enrollment, and 
12 trials are ongoing.
Tolvaptan was approved by the United States (US) Food and Drug 
Administration (FDA) on 19 May 2009, by the European Medicines 
Agency (EMA) on 03 Aug 2009, and subsequently in 11 other 
countries for the treatment of specific forms of hyponatremia.  
Tolvaptan was approved by the Japanese Ministry of Health, 
Labour, and Welfare (MHLW) on 27 Oct 2010 for the adjunct 
treatment of volume overload in heart failure when adequate 
response is not obtained with other diuretics; in September 2013 for 
body fluid retention in hepatic cirrhosis when adequate response is 
not obtained with other diuretics; and in March 2014 for suppression 
of progression of autosomal dominant polycystic kidney disease 


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(ADPKD) with increased kidney volume and a rapid rate of 
increase.  Phase 3 development for hepatic edema has been 
completed in China.  Tolvaptan is also being developed for the 
treatment of ADPKD in the US and multinationally; for the adjunct 
treatment of chronic renal failure treated with peritoneal dialysis and 
hematodialysis or hemodiafiltration, and for carcinomatous edema 
in Japan; and for cardiac edema in China and Taiwan.  As of 31 Mar 
2014, 87 trials had been completed, 4 trials were terminated because 
of slow enrollment, and 10 trials were ongoing. More information 
is available in the IB.
Section 1.2.1 
Pharmacokinetics
/Pharmacodynam
ics
Since inception of the program, a total of 45 phase 1 trials have been 
completed with tolvaptan (as of 31 Mar 2013) in healthy subjects or 
special populations in Japan, the United Kingdom, China, Korea, 
Argentina, and the US.
Since inception of the program, a total of 46 phase 1 trials have been 
completed with tolvaptan (as of 31 Mar 2014) in healthy subjects or 
special populations in Japan, the United Kingdom, China, Korea, 
Argentina, and the US. One phase 1 trial is ongoing.
Section 1.2.2 
Clinical Efficacy
Eleven trials involving either exclusive evaluation of adult subjects 
with hyponatremia (8 trials in which all subjects had hyponatremia) 
or substantial subpopulations of subjects with hyponatremia (3 CHF 
trials - not all subjects in these trials had hyponatremia) have been 
completed.  These 11 trials have included a total of 
804 hyponatremic subjects exposed to tolvaptan in doses ranging 
from 5 to 90 mg (4 subjects randomized to tolvaptan did not receive 
trial medication, 2 subjects in Trial 156-02-235 [SALT 1] and 
2 subjects in Trial 156-97-204); 480 subjects were from the 8 trials 
in which all subjects had hyponatremia and 324 subjects were from 
the 3 CHF trials who also had hyponatremia.  Two trials in subjects 
with hyponatremia are ongoing as of the IB cutoff date.  The 
hyponatremia-specific population for these trials was subjects with 
nonhypovolemic, nonacute hyponatremia arising from a variety of 
etiologies including heart failure, cirrhosis, SIADH, and others.  
Efficacy results from these completed trials can be found in the IB.
Briefly, in clinical trials, tolvaptan has consistently been shown to 
improve or normalize serum sodium concentrations in hyponatremic 
subjects, regardless of etiology.  In clinical trials in subjects with 
volume overload and hyponatremia, the effect of tolvaptan on serum 
sodium is combined with a reduction in fluid overload, as shown by 
Thirteen trials involving either exclusive evaluation of subjects with 
hyponatremia (10 trials in which all subjects have hyponatremia and 
a long-term extension trial) or substantial subpopulations of subjects 
with hyponatremia (3 CHF trials - not all subjects in these trials had 
hyponatremia,) have been conducted.
Briefly, in clinical trials, tolvaptan has consistently shown to 
improve or normalize serum sodium concentrations in hyponatremic 
subjects, regardless of etiology.  In clinical trials in subjects with 
volume overload and hyponatremia, the effect of tolvaptan on serum 
sodium is combined with a reduction in fluid overload, as shown by 
greater decreases in body weight compared to placebo.  
Additionally, subjects with liver disease responded to higher doses 
of tolvaptan with reductions in body weight.
...
The primary efficacy endpoints for the SALT 1 and 2 trials were the 
average daily AUC of change from baseline in serum sodium 
concentration up to Day 4 and up to Day 30.  For both primary 
endpoints, the difference between the treatment groups were highly 
statistically significant (p < 0.0001), and demonstrated that serum 


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greater decreases in body weight as compared to placebo.
...
The primary efficacy endpoints for the SALT 1 and 2 trials were the 
average daily AUC of change from baseline in serum sodium 
concentration up to Day 4 and up to Day 30.  For both primary 
endpoints, the difference between the treatment groups were highly 
statistically significant (p < 0.0001), and demonstrated that serum 
sodium concentrations increased more with tolvaptan than placebo 
over the first 4 days and the entire 30 days.  Significance was seen 
in both mild and severe hyponatremia subgroups (p < 0.001).  On 
stopping tolvaptan therapy, sodium concentrations fell to the level 
of placebo concentrations (see Figure 1.2.2-1).
sodium concentrations increased more with tolvaptan than placebo 
over the first 4 days and the entire 30 days.  Significance was seen 
in both mild and severe hyponatremia subgroups (p < 0.001).  When 
tolvaptan therapy was stopped, serum sodium concentrations fell to 
the level of placebo concentrations (Figure 1.2.2-1) but recovered 
upon resumption of tolvaptan therapy (Figure 1.2.2-2).
Figure 1.2.2-2
New figure added 
Section 1.3 
Known and 
Potential Risks 
and Benefits
As of 31 Mar 2013, 6,794 adult subjects have been exposed to oral 
doses of tolvaptan in 82 completed or terminated tolvaptan trials in 
the US, Europe, South America, and Asia:  1,047 healthy subjects, 
37 subjects with renal impairment (phase 1 trial), 3,115 subjects in 
trials for CHF, 425 subjects in trials for hyponatremia, 961 subjects 
in the pivotal long-term ADPKD trial, 137 subjects in short-term 
trials for ADPKD or renal impairment, 217 subjects with cardiac 
edema, and 855 subjects with hepatic edema.  Additionally, 
14 healthy adult subjects were exposed to a single 1-mg IV dose of 
tolvaptan in a phase 1 bioavailability trial (Trial 156-05-254) in the 
US.
The most commonly reported treatment-emergent adverse events 
(TEAEs; > 5% incidence) in hyponatremia trials for subjects treated 
with tolvaptan were thirst, dry mouth, peripheral edema, nausea, 
fatigue, dizziness, pollakiuria, diarrhea, headache, constipation, and 
pyrexia.  The most commonly reported TEAE (by > 5% incidence) 
in hyponatremia trials for subjects treated with placebo were 
peripheral edema, diarrhea, dyspnea, vomiting, fatigue, headache, 
diarrhea, and nausea.  The IB provides a thorough review of the 
adverse events (AEs) experienced with this compound during 
As of 31 Mar 2014, pooled exposure data are available from 
88 trials, including 7201 subjects worldwide who were exposed to 
oral doses of tolvaptan.  The extent of exposure to oral tolvaptan by 
dose in the pooled database (N = 7201) comprises 3115 subjects in 
trials for heart failure, 511 subjects in trials for hyponatremia, 
961 subjects in the pivotal long-term ADPKD trial, 270 subjects in 
short-term trials for ADPKD or renal impairment, 391 subjects in 
trials for cardiac edema, 855 subjects in trials for hepatic edema, 
37 subjects with renal impairment in a phase 1 trial, and 
1061 healthy subjects in clinical pharmacology trials. 
The most commonly reported TEAEs (by > 10% incidence and 
greater than placebo) in healthy subjects treated with tolvaptan were
thirst, pollakiuria, and headache.  Headache was the most commonly 
reported TEAE in the placebo subjects.
The hyponatremia program comprised 835 subjects from 12 short-
term trials involving either exclusive evaluation of subjects with 
hyponatremia (9 trials) or substantial subpopulations of subjects 
with hyponatremia (3 CHF trials). The 511 subjects in the 
hyponatremia trials were exposed to oral tolvaptan doses ranging 


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clinical trials.
Analyses of the completed 3-year pivotal Trial 156-04-251 
(double-blind, placebo-controlled trial to determine long-term safety 
and efficacy of oral tolvaptan in adult subjects with ADPKD) have 
revealed new and important safety information.  In this trial, a new 
signal for imbalanced elevations of liver transaminases in ADPKD 
subjects receiving tolvaptan compared with placebo was detected 
and formally adjudicated by an expert panel blinded to treatment.
Based on the analyses of combined central and local laboratory data, 
a total of 3 tolvaptan subjects in the ADPKD program (2 in Trial 
156-04-251 and one in the ongoing extension Trial 156-08-271) 
were identified as meeting Hy’s Law laboratory criteria (ie, alanine 
transaminase [ALT] or aspartate transaminase [AST] > 3 times the 
upper limit of normal [ULN] accompanied by total bilirubin 
> 2 ULN with the elevated total bilirubin occurring within 30 days 
after the transaminase elevation).  Based on review of the data from 
the adjudicated subjects, the transaminase elevations associated with 
tolvaptan treatment were reversible (ie, returned to 3 ULN 
typically within 1 to 4 months), and were not associated with 
fulminant liver failure, or permanent liver injury or dysfunction.
No association with tolvaptan dose or exposure was found.  The 
results do not appear to suggest an association between tolvaptan 
and age or gender with respect to an increased risk of potential liver 
injury.
...
In clinical trials, tolvaptan consistently has shown a beneficial effect 
in hyponatremic subjects by improving serum sodium 
concentrations, in many cases to normalization.  In subjects with 
heart failure, tolvaptan has consistently shown a beneficial effect by 
improving fluid balance through the induction of increased urine 
volume.  In subjects with volume overload and hyponatremia 
from 5 to 60 mg, for a total of 8339 days of exposure. In the 
9 hyponatremia trials, the most commonly reported TEAEs 
(> 5% incidence) in the tolvaptan subjects were thirst, dry mouth, 
peripheral oedema, nausea, dizziness, fatigue, constipation, 
headache, ascites, diarrhoea, pollakiuria, asthenia, hypotension, 
pyrexia, and hypokalaemia.  The most commonly reported TEAEs 
(> 5% incidence) in the placebo subjects were peripheral oedema, 
diarrhoea, headache, ascites, vomiting, dyspnoea, nausea, and 
hypotension.  The IB provides a thorough review of the adverse 
events (AEs) experienced with this compound during clinical trials.
Analyses of the completed 3-year pivotal Trial 156-04-251 
(double-blind, placebo-controlled trial to determine long-term safety 
and efficacy of oral tolvaptan in adult subjects with ADPKD) have 
revealed new and important safety information.  In this trial, a new 
signal for imbalanced elevations of liver transaminases in subjects 
with ADPKD receiving tolvaptan compared with placebo was 
detected and formally adjudicated by an expert panel blinded to 
treatment.
Based on the analyses of combined central and local laboratory data, 
a total of 3 tolvaptan subjects in the ADPKD program (2 in Trial 
156-04-251 and 1 in the ongoing extension Trial 156-08-271) were 
identified as meeting Hy’s Law laboratory criteria (ie, alanine 
transaminase [ALT] or aspartate transaminase [AST] > 3 times the 
upper limit of normal [ULN] accompanied by total bilirubin [BT]
> 2 ULN with the elevated BT occurring within 30 days after the 
transaminase elevation).  Based on review of the data from the 
adjudicated subjects, the transaminase elevations associated with 
tolvaptan treatment were reversible (ie, returned to 3 ULN 
typically within 1 to 4 months), and were not associated with 
fulminant liver failure, or permanent liver injury or dysfunction.
No association with tolvaptan dose or exposure was found.  The 
results do not appear to suggest an association between tolvaptan 
and age or sex with respect to an increased risk of potential liver 


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receiving optimal standard heart failure therapy, the effect of 
tolvaptan on serum sodium is combined with a reduction in fluid 
overload, as shown by greater decreases in body weight as 
compared with placebo.  In subjects hospitalized with worsening 
heart failure and symptoms of fluid overload, tolvaptan treatment, in 
addition to continued conventional therapy, including diuretics, 
increased weight reduction, improved subject-assessed dyspnea and 
pedal edema, normalized serum sodium concentrations in subjects 
with hyponatremia, and maintained renal function in comparison to 
placebo.
Additional safety and prescribing information can be found in the 
product label, which is attached to the IB.  To date, no clinical trials 
in children have been conducted with tolvaptan.
injury.
...
In clinical trials, tolvaptan consistently has shown a beneficial effect 
in hyponatremic subjects by improving serum sodium 
concentrations, in many cases to normalization.  In subjects with 
heart failure, tolvaptan has consistently shown a beneficial effect by 
improving fluid balance through the induction of increased urine 
volume.  In subjects with volume overload and hyponatremia 
receiving optimal standard heart failure therapy, the effect of 
tolvaptan on serum sodium is combined with a reduction in fluid 
overload, as shown by greater decreases in body weight as 
compared with placebo.  In subjects hospitalized with worsening 
heart failure and symptoms of fluid overload, tolvaptan treatment, in 
addition to continued conventional therapy including diuretics, 
increased weight reduction, improved subject-assessed dyspnea and 
pedal edema, normalized serum sodium concentrations in subjects 
with hyponatremia, and maintained renal function in comparison to 
placebo.
Additional safety information can be found in the IB.  To date, no 
clinical trials in children have been conducted with tolvaptan.
Section 2 Trial 
Rationale and 
Objectives
No text in this section.
This trial will consist of a core safety follow-up component and an 
optional tolvaptan treatment component. The rationale and 
objectives of the 2 components of the trial are described in 
Section 2.1.1 (core safety follow-up component) and Section 2.1.2
(optional tolvaptan treatment component). 
Section 2.1 Trial 
Rationale
The purpose of this trial is to follow children and adolescent 
subjects who have previously participated in a trial of titrated oral 
tolvaptan for euvolemic or hypervolemic hyponatremia and to 
examine the safety and efficacy of tolvaptan when used for both 
multiple short-term treatments and longer chronic treatments in 
children and adolescents with euvolemic or hypervolemic 
hyponatremia secondary to various underlying etiologies.
Up to 140 potential subjects are to be enrolled in the tolvaptan 
pediatric trials for hyponatremia (ie, Trials 156-08-276, 156-12-205, 
No text in this section.


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and 156-13-207).  This trial will follow subjects for 6 months 
following treatment in the previous trial.
Based on the information from Otsuka’s pediatric hyponatremia 
advisory board, although short-term treatment is expected, repeat 
treatments over time may be necessary.  Therefore, some of the 
subjects may require a regimen with tolvaptan to supplement 
treatment following the completion of the earlier short-term 
efficacy, safety, PK, and PD trials (ie, Trials 156-08-276, 156-12-
205, or 156-13-207).
Recruitment for this proposed trial will be exclusively from Trials 
156-08-276, 156-12-205, or 156-13-207 after subjects meet the 
entry criteria.
Section 2.1.1 
Core Safety 
Follow-up 
Component
New section in this amendment.
The primary purpose of this component of this trial is to follow 
children and adolescent subjects who have previously participated in 
a trial of titrated oral IMP (tolvaptan in Trial 156-08-276; tolvaptan 
or placebo in Trial 156-13-207 or Trial 156-12-205) for dilutional 
(euvolemic or hypervolemic) hyponatremia regardless of their 
treatment status with tolvaptan.  The minimum duration of safety 
follow-up will be 6 months.
Section 2.1.2 
Optional 
Tolvaptan 
Treatment 
Component
New section in this amendment.
Children and adolescent subjects who have previously participated 
in a tolvaptan hyponatremia trial (Trials 156-08-276, 156-13-207, 
or 156-12-205) who meet the eligibility criteria for treatment with 
tolvaptan may be eligible for one or more additional cycles of 
tolvaptan treatment.  
Depending upon clinical need and the investigator’s discretion, 
subjects in the core safety follow-up component may receive no 
treatment, be treated per the local standard of care for hyponatremia, 
or start treatment with tolvaptan.  Based on the various underlying 
etiologies contributing to hyponatremia, the need for treatment may 
differ per individual subject.  Therefore, some of the subjects may 
require a regimen with tolvaptan to supplement treatment following 
the completion of the earlier short-term efficacy, safety, PK, and PD 


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trials (Trials 156-08-276, 156-13-207, or 156-12-205), and this 
protocol is designed to accommodate short-term, long-term, and 
repeated tolvaptan treatment cycles as necessary. Each tolvaptan 
treatment cycle will consist of a titration phase and a maintenance 
phase, with a planned discontinuation of treatment on Day 30 for 
assessment of the need for continued treatment. After 
demonstrating the need for continued tolvaptan treatment beyond 
the first 30 days, subjects taking concomitant medications, with 
underlying conditions, or receiving treatments that contraindicate 
the discontinuation of tolvaptan treatment may be exempted from 
treatment discontinuation.  
Section 2.2 
Dosing Rationale
Eligible subjects with a demonstrated clinical need will be dosed 
with tolvaptan based on age, weight, and the use of CYP3A4 
inhibitors.  Subjects < 2 years of age or < 10 kg will be excluded 
until the availability of a liquid formulation.  Subjects 2 years of 
age and weighing 10 to < 20 kg will receive an oral once daily 
dose of tolvaptan starting as a 3.75-mg spray-dried tablet.  Subjects 
weighing 20 to 50 kg, inclusive, will receive an oral once daily dose 
of tolvaptan starting as a 7.5-mg spray-dried tablet.  Subjects 
weighing > 50 kg will receive an oral once daily dose of tolvaptan 
starting as a 15-mg spray-dried tablet.  For subjects weighing 
20 kg and taking moderate inhibitors of CYP3A4, a half-dose will 
be used (3.75 or 7.5 mg, by weight).  For subjects weighing > 50 kg 
and taking potent inhibitors of CYP3A4, a one-quarter dose will be 
used (3.75 mg).  Subjects weighing < 20 kg and who are taking any 
CYP3A4 inhibitors will be excluded from the trial until such time 
that an alternate dosing formulation is available.
It is estimated that subjects 6 years of age weigh approximately 
25 kg.  A 7.5-mg dose in a subject weighing 25 kg would be 
0.3 mg/kg.  For a subject weighing 50 kg, a 7.5-mg dose would be a 
0.15-mg/kg dose.  For a 15-mg dose, the corresponding body 
weights for 0.3- and 0.15-mg/kg doses would be 50 to 100 kg.
In the optional tolvaptan treatment component of the trial, eligible 
subjects with a demonstrated clinical need will be dosed with 
tolvaptan based on age, weight, and the use of CYP3A4 inhibitors.  
Subjects < 2 years of age, or < 10 kg, or those who cannot swallow 
a tablet, will be excluded until an oral liquid formulation becomes 
available.  Subjects 2 years of age and weighing 10 to < 20 kg 
will receive an oral QD dose of tolvaptan starting as a 3.75-mg 
spray-dried tablet.  Subjects weighing 20 to 50 kg, inclusive, will 
receive an oral QD dose of tolvaptan starting as a 7.5-mg spray-
dried tablet.  Subjects weighing > 50 kg will receive an oral QD 
dose of tolvaptan starting as a 15-mg spray-dried tablet.  For 
subjects weighing 20 kg and taking moderate inhibitors of 
CYP3A4, a half-dose will be used (3.75 or 7.5 mg, by weight).  For 
subjects weighing > 50 kg and taking potent inhibitors of CYP3A4, 
a one-quarter dose will be used (3.75 mg).  Subjects weighing 
< 20 kg and who are taking any CYP3A4 inhibitors will be 
excluded from the trial until such time that an oral liquid 
formulation is available.
It is estimated that subjects 6 years of age weigh approximately 
25 kg. Starting tolvaptan tablet doses as mg/kg of body weight are 
shown in Table 2.2-1.
Table 2.2-1 
Starting 
Tolvaptan Tablet 
New table in this amendment.


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Doses as mg/kg 
Body Weight
Table 2.2-1
Starting Tolvaptan Tablet Doses as 
mg/kg of Body Weight
Tolvapt
an 
Tablets
Tolvaptan Doses as mg/kg
BW of 
10 kg
BW of 
20 kg
BW of 
50 kg
BW of 
70 kg
BW of 
100 kg
3.75 mg
0.375
0.19
-
-
-
7.5 mg
-
0.375
0.15
-
-
15 mg
-
-
0.30
0.21
0.15
BW = body weight
Section 2.3 
Objectives
The objectives of this trial are:

For all subjects:  To evaluate the post-treatment safety 
follow-up of children and adolescent subjects with 
euvolemic or hypervolemic hyponatremia who have 
previously participated in a trial of titrated oral tolvaptan.

For subjects who receive tolvaptan:  To demonstrate that 
tolvaptan safely and effectively achieves and maintains 
increased serum sodium concentrations in children and 
adolescent subjects with euvolemic or hypervolemic 
hyponatremia when used for both multiple short-term 
treatments and/or longer chronic treatments.
The objectives of this trial are:

For all subjects (core safety follow-up component):  To 
evaluate the post-treatment safety follow-up of children 
and adolescent subjects with dilutional (euvolemic or 
hypervolemic) hyponatremia who have previously 
participated in a trial of titrated oral IMP (tolvaptan in 
Trial 156-08-276, tolvaptan or placebo in 
Trials 156-13-207 or 156-12-205).

For subjects who receive tolvaptan (optional tolvaptan 
treatment component):  To demonstrate that tolvaptan 
safely and effectively achieves and maintains increased 
serum sodium concentrations in children and adolescent 
subjects with dilutional (euvolemic or hypervolemic) 
hyponatremia when used for both multiple short-term 
treatments and/or longer chronic treatments.
Section 3.1 
Type/Design of 
Trial
See Figure 3.1-1 for a schematic of the trial design.
This is an observational follow-up trial in children and adolescents 
who have previously participated in a trial of titrated oral tolvaptan 
for euvolemic or hypervolemic hyponatremia.  Subjects who were 
enrolled in at least one of the tolvaptan pediatric efficacy, safety, 
PK, and PD trials for hyponatremia (ie, Trials 156-08-276, 
156 -12-205, or 156-13-207) are eligible for enrollment in this trial.  
Enrollment in this trial should directly follow completion or 
This trial consists of 2 components, a 6 month safety follow-up 
study and an embedded optional tolvaptan treatment study for 
subjects. The 2 components are described below and illustrated in 
Figure 3.1-1.


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discontinuation of the previous trial.  The end of trial visit in the 
previous trial will serve as the Baseline Visit in this trial.  Subjects 
will be followed once a month for 6 months, alternating between 
telephone contact and in-clinic visits, to clinically evaluate children 
and adolescent subjects with hyponatremia, regardless of the need 
for treatment.  If a subject has a clinical need for treatment with 
tolvaptan, the subject may be screened for eligibility to be dosed 
within this trial.  The subject must have been off of treatment with 
the investigational medicinal product (IMP) for a minimum of 
7 days following the end of treatment in the previous trial to assess 
the subject’s clinical need for dosing.  Subjects can be treated with 
tolvaptan during and/or after the initial 6-month follow-up period.


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Old Text: Figure 3.1-1
Figure 3.1-1
Trial Design Schematic
aSubjects must be 2 years of age and weigh 10 kg until development of a liquid formulation is complete.


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New Text: Figure 3.1-1
Figure 3.1-1
Trial Design Schematic


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Section 3.1.1 
Core Safety 
Follow-up 
Component
Section 3.1.1 Tolvaptan Treatment
Pediatric and adolescent subjects who are diagnosed with euvolemic 
or hypervolemic hyponatremia (serum sodium < 130 mmol/L) that 
persists despite initial standard background therapy (eg, including 
fluid restriction) are eligible to be screened for dosing with 
tolvaptan.  All potential subjects must also be deemed by the 
investigator as likely to benefit from a therapy that raises serum 
sodium levels.  The investigator is required to call the medical 
monitor to discuss the appropriateness of dosing for subjects who 
discontinued from the previous trial early or demonstrated a lack of 
response, but have a clinical need for tolvaptan.
Since hyponatremia in this patient population can often be transient 
and/or may be secondary to hypovolemic states, potential subjects 
will be screened for hyponatremic histories as well as clinically 
evaluated to rule out such cases.  For the purpose of determining 
eligibility for treatment with tolvaptan within this protocol, 
persistent hyponatremia will be defined as serum sodium 
assessments < 130 mmol/L documented as present for at least 
48 hours.  Specifically, subjects must have at least 2 serum sodium 
assessments < 130 mmol/L drawn at least 12 hours apart.  These 
values can be documented using historical values previously 
obtained as per standard of care.  A third (immediate [STAT]) 
serum sodium assessment < 130 mmol/L, which will serve as the 
baseline value for efficacy endpoints, is to be obtained within 
3 (1) hours of the first dose of trial medication.  Additional 
qualification assessments will be performed as per etiology of 
hyponatremia.  The first dose of trial medication will be 
administered upon successful completion of all pretreatment 
baseline procedures.
As stated above, all eligible subjects will be evaluated to determine 
a minimal 48-hour history of hyponatremia to establish chronicity.  
However, it remains the responsibility of the investigator to 
determine the etiology of the hyponatremia and to assess the volume 
Section 3.1.1 Core Safety Follow-up Component
The core safety follow-up component of the trial is a 6-month 
period in which pediatric subjects (children and adolescents) who 
previously participated in a trial of titrated IMP (tolvaptan in 
Trial 156-08-276; tolvaptan or placebo in Trial 156-13-207 or 
156-12-205) will be followed once a month (alternating clinical trial 
site visits and telephone calls), regardless of the need for treatment 
for hyponatremia, to assess long term-safety of tolvaptan.  This trial 
should directly follow completion or discontinuation of the previous 
trial. The final laboratory assessments performed in the previous 
trial of titrated oral IMP may serve as the baseline laboratory 
assessments in this trial, if possible. 


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status as appropriate for each subject using diagnostic tests or 
evaluations (eg, fractional excretion of sodium [FENa], fractional 
excretion of urate [FE urate], urine osmolality, serum osmolality) 
employed in the usual clinical course of care.
Eligible subjects will receive daily doses of oral tolvaptan based on 
individual titration results and clinical need.  Subjects will be 
required to be in a hospital setting during initiation or up-titration of 
administration of tolvaptan.  If a subject is not expected to receive a 
higher dose of tolvaptan, continued administration can be done 
outside of the hospital setting.  Regardless of whether a subject is in 
the hospital setting or not, the subject should return to the clinical 
site for assessment of serum sodium concentrations on an ongoing 
basis (see Section 3.1.1.1) to monitor the stability of his/her 
hyponatremia or his/her achievement of normal or clinician-directed 
target range serum sodium.  Some subjects are expected to need to 
remain on a stable dose of tolvaptan to maintain clinician-directed 
target range serum sodium concentrations.  Treatment can continue 
per clinical need as determined by the investigator in consultation 
with the sponsor’s medical monitor.  Follow-up visits for safety and 
assessment of serum sodium concentrations can be adjusted per the 
guidelines in Section 3.1.1.1.
Upon achieving normal or clinician-directed target range serum 
sodium, subjects should be assessed for the need for ongoing 
treatment and then return to the clinic site for serum sodium 
assessments at 48 (4) hours and 7 (+ 1) days after the last dose of 
tolvaptan.  Up-titration of tolvaptan doses can occur once daily and 
will be based on serum sodium levels at > 20 hours following 
initiation of therapy and each subsequent dose; up-titration may not 
occur within 20 hours of the previous dose.
Treatment can be discontinued and reinitiated as needed per 
individual subject’s need (eg, during chemotherapy treatments).  If 
subjects are off of tolvaptan treatment for 48 hours, reinitiation of 
treatment will require reassessment of eligibility criteria and should 


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begin in a hospital setting.  Tolvaptan should be titrated with regular 
serum sodium assessments (see Section 3.1.1.1 and Section 3.2.1).  
After discontinuation of tolvaptan, serum sodium should be assessed 
at 48 (4) hours and 7 (+ 1) days post-last dose.
Once a subject becomes legal adult age, the subject will be 
reconsented as appropriate and will be allowed to continue in the 
trial until tolvaptan becomes otherwise available to the subject.  All 
pediatric subjects will be allowed to continue in the trial until 
tolvaptan becomes approved for the pediatric population.
Section 3.1.1.1 
Core Safety 
Follow-up 
Component 
Phases
Section 3.1.1.1 Treatment Follow-up

Subjects should have serum sodium assessments at a 
minimum of daily during the Titration Period.

During the Maintenance Period, for Months 1 to 3, serum 
sodium concentrations should be assessed at a minimum of 
every 2 weeks (2 days).

During the Maintenance Period, from Month 4 onward for 
consecutive treatment, subjects should return to the site 
minimally once per month (2 days) for assessment of serum 
sodium concentrations.

Alanine transaminase and AST should be assessed once a 
month while subjects are on tolvaptan.

A PK blood sample should be collected after 8 consecutive 
weeks of treatment.

If the principal investigator (PI) notes any other significant 
clinical change during the treatment cycle, additional serum 
sodium testing should be performed to ensure appropriate 
treatment of each subject.
Section 3.1.1.1 Core Safety Follow-up Component Phases
Subjects enrolled in this trial are required to complete 7 visits 
regardless of their treatment status with tolvaptan. The Baseline 
Visit as well as Month 2, 4 and 6 Visits are performed in clinic 
while Month 1, 3 and 5 Visits can be conducted via telephone.  
During the in clinic visits subjects are evaluated for relevant 
information.
Since all pediatric subjects (children and adolescents) who 
previously participated in a trial of titrated IMP (tolvaptan in 
Trial 156-08-276; tolvaptan or placebo in Trial 156-13-207 or 
156-12-205) are eligible to participate in this trial there is no 
screening phase.  Similarly, since the goal of the trial is to collect 
follow-up information for prior treatment there is no separate 
follow-up phase.
Section 3.1.2 
Optional 
Tolvaptan 
Treatment 
Component
New section in this amendment
Subjects enrolled in the 6-month core safety follow-up component 
may meet the criteria for treatment with tolvaptan. This subset of 
the study population may receive cycles of tolvaptan per clinical 
need to treat their hyponatremia. If a subject has a clinical need for 
treatment with tolvaptan, the subject may be screened for eligibility 
to be dosed within this trial. The subject must have been off 


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treatment with the IMP for 7 days following the end of treatment in 
the previous trial of titrated oral IMP (tolvaptan in Trial 156-08-276, 
tolvaptan or placebo in Trials 156-13-207 and 156-12-205) to assess 
the subject’s clinical need for dosing.  Eligibility for tolvaptan 
treatment must be determined between Day -4 and Day -1 of each 
dosing cycle.  Subjects can be treated with tolvaptan during and/or 
after the 6-month core safety follow-up component after evaluating 
the subject using the criteria outlined in Appendix 5.
Thirty days after the start of tolvaptan treatment, all subjects 
receiving tolvaptan will discontinue treatment for up to 72 hours, 
during which the need for continuing treatment with tolvaptan will 
be reassessed. Subjects who resume dosing can do so at the same 
dose or a lower dose without having to go through the full titration 
cycle again. Subjects who have a dosing discontinuation of 
> 72 hours must repeat the full titration cycle in a hospital setting.
The optional tolvaptan treatment component of the trial does not 
have a fixed stopping point. Subjects who have an ongoing need for 
treatment can continue to receive tolvaptan per the investigator’s 
clinical judgment until they no longer have a need for treatment or 
all subjects have completed the 6 month Core Follow-up 
Component of the trial. Subjects who terminate tolvaptan treatment 
will have follow-up visits at 24 hours (4 hours), and at 
7 (1) days post-last dose, and a telephone call at 14 days 
(+ 2 days) post-last dose. Additional follow-up contacts will be 
performed on a regular basis until the end of the trial.
Section 3.1.2.1 
Optional 
Tolvaptan 
Treatment Cycles
New section in this amendment
This section describes the expectations for subjects participating in a 
treatment cycle of the Optional Tolvaptan Treatment Component.  
The minimum frequency of recurring laboratory assessments during 
the optional tolvaptan treatment component is shown in Appendix 6.


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Section 3.1.2.1.1 
Screening 
(Pretreatment 
Baseline)
New section in this amendment
A subject who requires tolvaptan treatment can be treated for as 
many cycles as deemed necessary by the investigator, and the 
duration of treatment cycles may vary per the investigator’s 
assessment of clinical need.  Regardless of the number of treatment 
cycles and the duration of tolvaptan treatment in each cycle, 
optional tolvaptan treatment cycles will consist of a Titration Phase, 
a Maintenance Phase, and a Follow-up Phase.  Subjects 
participating in the 6-month core safety follow-up component may 
become eligible for tolvaptan treatment at any time if they have 
dilutional (euvolemic or hypervolemic) hyponatremia (serum 
sodium < 130 mEq/L [mmol/L]).  The investigator is required to 
call the medical monitor to discuss the appropriateness of tolvaptan 
treatment for subjects who discontinued from the previous trial of 
titrated oral IMP (tolvaptan in Trial 156-08-276, tolvaptan or 
placebo in Trials 156-13-207 and 156-12-205) early or 
demonstrated a lack of response to tolvaptan, but have a 
demonstrated clinical need for tolvaptan.  
Since hyponatremia in this patient population can often be transient 
and/or may be secondary to hypovolemic states, potential subjects 
will be screened for hyponatremic histories as well as clinically 
evaluated to exclude such cases from the optional tolvaptan 
treatment component of the trial.  To be eligible for the optional 
tolvaptan treatment component of this protocol, subjects must have 
persistent dilutional (euvolemic or hypervolemic) hyponatremia, 
defined as serum sodium assessments < 130 mEq/L (mmol/L) that 
are documented for at least 48 hours after the final dose of IMP in 
the previous trial and prior to the planned initiation of tolvaptan 
titration in this trial.  These values can be documented using 
historical values previously obtained per standard of care.  A third 
(immediate [STAT]) serum sodium assessment < 130 mEq/L 
(mmol/L), which will serve as the final treatment qualification, 
management strategy, and baseline value for efficacy endpoints, is 
to be obtained within 2 to 4 hours of the first dose of tolvaptan.  
Additional qualification assessments will be performed per etiology 
of hyponatremia.


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Section 3.1.2.1.2 
Treatment 
Initiation and 
Maintenance
New section in this amendment
A subject who requires tolvaptan treatment can be treated for as 
many cycles as deemed necessary by the investigator, and the 
duration of treatment cycles may vary per the investigator’s 
assessment of clinical need.  Regardless of the number of treatment 
cycles and the duration of tolvaptan treatment in each cycle, 
optional tolvaptan treatment cycles will consist of a Titration Phase, 
a Maintenance Phase, and a Follow-up Phase.  The schedule of 
assessments for the optional tolvaptan treatment component is 
shown in Section 3.7.3.
The first dose of tolvaptan will be administered upon successful 
completion of all pretreatment baseline procedures.  Subjects will 
enter a titration phase and follow the titration schedule outlined in 
Section 3.2.1.2.  Eligible subjects will receive daily doses of oral 
tolvaptan based on individual titration results and clinical need.  
Subjects will be required to be in a hospital setting during initiation 
or titration of tolvaptan.  If a subject is not expected to receive a 
higher dose of tolvaptan, continued administration can be done 
outside of the hospital setting.  Titration of tolvaptan doses can 
occur once daily and will be based on serum sodium levels at 
24 hours following initiation of therapy and each subsequent dose. 
Titration of tolvaptan doses is limited to twice the previous dose, 
cannot exceed the maximum dose per body weight (mg/kg), and 
may not occur within 20 hours of the previous dose.
Regardless of whether a subject is in the hospital setting or not, the 
subject should return to the clinical trial site for assessment of serum 
sodium concentrations on an ongoing basis to monitor the stability 
of his/her hyponatremia or his/her achievement of normal or 
clinician-directed target range serum sodium.  Some subjects are 
expected to need to remain on a stable dose of tolvaptan to maintain 
target-range serum sodium concentrations as directed by the 
clinician.  Treatment can continue per clinical need as determined 
by the investigator in consultation with the medical monitor.  
Follow-up visits for safety and assessment of serum sodium 
concentrations can be adjusted. 


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During the first 30 days of treatment subjects should have serum 
sodium assessments at a minimum of once daily during the Titration 
Phase on Day 1 up to Day 4 of treatment, and at a minimum of once 
weekly thereafter once on a stable dose (ie, on Days 7, 14, 21, and 
28). 
After the first 30 consecutive days of treatment, all subjects who 
receive tolvaptan will be assessed for the need to continue treatment 
(Section 3.7.3.2.4).  However, subjects may be assessed, per 
investigator’s discretion, for the need for ongoing treatment with 
tolvaptan at any time point during treatment.  Subjects who 
demonstrate a need for tolvaptan treatment may continue treatment 
to maintain the normal or clinician-directed target range serum 
sodium.  Procedures for reinitiation of tolvaptan treatment for 
subjects with a clinical need per the investigator’s assessment are 
described in Section 1.1.1.
Tolvaptan treatment can be discontinued and reinitiated as needed 
per individual subject’s need (eg, during chemotherapy treatments).  
If subjects are off tolvaptan treatment for> 72 hours, reinitiation of 
treatment will require reassessment of eligibility criteria and will 
begin in a hospital setting.  Tolvaptan should be titrated with regular 
serum sodium assessments (Section 3.2.1.2 and Section 3.7.4.1).  
During the second consecutive month of treatment, serum sodium 
concentrations should be assessed at a minimum of every 2 weeks 
(2 days).
Once a subject has been treated for 2 months, if no new titration 
occurs, then at the beginning of third month, subjects can be 
considered to have entered the maintenance phase.  They should 
return to the clinical trial site at a minimum of once per month 
(2 days) for a trial visit and an assessment of serum sodium 
concentrations.  ALT, AST, and BT should be assessed, and a 
pregnancy test performed (on female subjects 12 years of age and 


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female subjects < 12 years of age if menstruation has started), once 
a month while subjects are on tolvaptan.
A PK blood sample should be collected after 8 consecutive weeks of 
treatment, which may include a discontinuation of 72 hours to 
assess the subject’s need for continued treatment. 
If the principal investigator (PI) notes any other significant clinical 
change during the treatment cycle, additional serum sodium testing 
should be performed to ensure appropriate treatment of each subject.
Section 3.1.2.1.3 
Follow-up Phase 
(End of 
Tolvaptan 
Treatment Cycle)
New section in this amendment
Subjects who discontinue tolvaptan treatment in the optional 
tolvaptan treatment component per the investigator’s decision will 
return to the clinical trial site for serum sodium assessments at 
24 (4) hours and at 7 (1) days post-last dose, and will receive 
follow-up telephone calls at 14 (+2) days and every 3 months 
(2 weeks) post-last dose. In the Follow-up Phase (ie, at the end of 
Month 6 or at the end of the tolvaptan treatment), subjects should 
have serum sodium assessments at 24 (4) hours and 7 (+ 1) days, 
and 14 (+2) days post-last dose.  ALT, AST, and BT should be 
assessed at 24 (4 hours) post-last dose, if more than 1 month has 
elapsed since LFTs were performed. An IRE form will be 
completed if the subject is a potential Hy’s Law case (see 
Section 5.4).  Potential Hy’s Law cases will be followed up until the 
ALT, AST, and BT values are within normal limits.
Section 3.2 
Treatments
Subjects enrolled in this trial will not receive IMP unless they 
demonstrate a clinical need as determined by the investigator and 
meet the eligibility criteria for treatment.  If a subject has a clinical 
need for tolvaptan, the subject may be screened for eligibility to be 
dosed with tolvaptan.  The subject must have been off of treatment 
with IMP for a minimum of 7 days following the end of treatment in 
the previous trial to assess the subject’s clinical need for treatment 
with tolvaptan.
Tolvaptan will initially be supplied as 3.75-, 7.5-, 15-, and 30-mg 
The Core Safety Follow-up Component of the trial does not contain 
any trial specific treatments.  However, subjects have the 
opportunity to receive treatment in the Optional Tolvaptan 
Treatment Component in which case the information outlined in the 
remainder of Section 3.2.1applies.
For all subjects enrolled in the core safety follow-up component of 
the trial, the need for initiation of tolvaptan treatment will be 
assessed per protocol serum sodium guidelines and the duration of 
tolvaptan administration will determined by the PI per the subject’s 


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tablets.  Upon the availability of a liquid formulation, the protocol 
will be amended to reflect additional dosing options.
Tolvaptan will be administered once daily orally with a dose 
proportional amount of water.  Doses of 15 mg tolvaptan will be 
given with 240 mL of water, 7.5 mg tolvaptan will be given with 
120 mL of water, and 3.75 mg tolvaptan will be given with 60 mL 
of water.  Tolvaptan will be initially administered in a hospital 
setting for each cycle.  Once the subject is maintaining a stable dose 
of tolvaptan, administration of the IMP can be done away from the 
clinic and regular assessments for safety will be performed.
The duration of administration of tolvaptan will be per medical need 
as determined by the PI.  Subjects may have short-term treatment 
(ie, a few days of treatment needed per episode of hyponatremia) or 
long-term treatment (ie, treatment for weeks to months with 
concomitant medication).
Subjects will be administered tolvaptan on an age- and weight-based 
scale.  Up-titration of tolvaptan doses can occur once daily and will 
be based on serum sodium levels at > 20 hours following initiation 
of therapy and each subsequent dose; up-titration may not occur 
within 20 hours of the previous dose.  A change in serum sodium 
4 mmol/L from baseline should warrant up-titration, which is 
limited to no more than twice the previous dose.

Subjects < 2 years of age or weighing < 10 kg are excluded 
until a liquid formulation is available.  Tolvaptan 
metabolism is primarily mediated by CYP3A4 and 
intestinal and hepatic concentrations of this enzyme 
increase following birth.  Developmental information from 
PK models of midazolam and cisapride, other CYP3A4 
substrates, in neonates and infants will be used to provide 
dosing recommendations for the liquid formulation when 
available.

Subjects 2 years of age and weighing 10 to < 20 kg will 
be given a 3.75-mg tablet on Day 1 with possible 
medical need. 


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up-titration to 7.5- and 15-mg tablet doses.

Subjects weighing 20 to 50 kg, inclusive, will be given a 
7.5-mg tablet on Day 1 with possible up-titration to 15- and 
30-mg tablet doses.

Subjects weighing > 50 kg will be given a 15-mg tablet on 
Day 1 with possible up-titration to 30- and 60-mg tablet 
doses.
For subjects weighing 20 kg and taking moderate inhibitors of 
CYP3A4, a half-dose will be used (3.75 or 7.5 mg, by weight).  For 
subjects weighing > 50 kg and taking potent inhibitors of CYP3A4, 
a one-quarter dose will be used (3.75 mg).  Subjects weighing 
< 20 kg and who are taking any CYP3A4 inhibitors will be 
excluded until such time that an alternate dosing formulation is 
available.
Subjects will have the opportunity to titrate as per medical need via 
the guidelines listed in Section 3.2.1 targeting a final sodium 
concentration between 135 and 140 mmol/L.  Titration guidelines 
are designed to ideally achieve a change in serum sodium 
concentration of at least 4 to 8 mmol/L/24 hours but not 
12 mmol/L/24 hours.
Subjects will receive daily doses of oral tolvaptan based on 
individual titration results and clinical need.  Treatment can 
continue per clinical need as determined by the investigator in 
consultation with the sponsor medical monitor and follow-up visits 
for safety and serum sodium assessments can be adjusted per the 
guidelines in Section 3.1.1.  If the subject’s serum sodium has 
reached the normal or clinician-directed target range, dosing may 
stop.  Initiation of tolvaptan treatment can be repeated as needed per 
individual subject’s need.  If subjects are off of tolvaptan treatment 
for 48 hours, reinitiation of treatment will require reassessment of 
the eligibility criteria.


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Section 3.2.1 
Optional 
Tolvaptan 
Treatment
Section 3.2.1. Titration Guidelines
The titration scheme is presented in Figure 3.2.1-1.
If serum sodium increases > 4 to < 8 mmol/L/24 hours, then the 
dose of tolvaptan should remain the same.  If serum sodium 
increases 8 mmol/L/24 hours or reaches a concentration 
140 mmol/L, the dose of tolvaptan should be held and the medical 
monitor should be called.  If serum sodium changes by 
4 mmol/L/24 hours and the subject is still below the therapeutic 
target for serum sodium (135 mmol/L), then the tolvaptan dose may 
be titrated up to the next scheduled dose appropriate to the subject’s 
body weight.  If at any point serum sodium or symptoms worsen or 
fail to improve and definitive therapy (eg, isotonic or hypertonic 
saline) is required, the subject will be withdrawn from the trial to 
receive “rescue therapy.”  These subjects will be withdrawn from 
trial treatment, but should continue to be followed as per protocol.  
The medical monitor should be contacted at any point if questions 
arise regarding titration.  The rationale for any up- or down-titration 
of tolvaptan must be documented.  Any initiation or titration of 
tolvaptan must occur in a hospital setting.  Subjects requiring 
ongoing treatment with tolvaptan may continue as needed per 
clinician’s discretion.
A dosing schedule for subjects is presented in Table 3.2.1-1.
Section 3.2.1 Optional Tolvaptan Treatment
No text in this section
Section 3.2.1.1 
Tablet 
Formulation
New section in this amendment
Tolvaptan tablets will be administered orally QD, preferably in the 
morning hours, with a dose- proportional amount of water.  Doses 
of 15 mg of tolvaptan will be given with 240 mL of water, 7.5 mg 
of tolvaptan will be given with 120 mL of water, and 3.75 mg of 
tolvaptan will be given with 60 mL of water.  Any initiation or 
titration of tolvaptan must occur in a hospital setting.
The maximum starting doses, by weight, for subjects are shown in 
Section 3.2.1.2 and are within the range previously used in trials 
involving adult hyponatremic subjects.


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Section 3.2.1.2 
Titration 
Guidelines for 
the Optional 
Tolvaptan 
Treatment 
Component
Section 3.2.2 Rescue Therapy
Subjects with worsening hyponatremia symptoms during the trial 
may receive rescue therapy.  Rescue therapy is defined as any 
hypertonic saline, isotonic saline (with or without diuretic for 
purpose of increasing the serum sodium level), 
plasmapheresis/dialysis, demeclocycline, urea, lithium, commercial 
vaptans, or any treatment intended to raise the level of serum 
sodium.
A subject requiring rescue therapy at any time after enrollment will 
be discontinued from the trial treatment prior to receiving rescue 
therapy and should continue to be followed as per protocol.  
Treatment may be reinitiated only per consultation with the 
sponsor’s medical monitor; however, subjects who have received 
rescue therapy secondary to inadequate response to tolvaptan will 
not be allowed to reinitiate tolvaptan treatment.  Sodium values 
drawn up to, but not after, the initiation of rescue therapy will be 
included in the calculation of the efficacy endpoint.
Section 3.2.1.2 Titration Guidelines for the Optional Tolvaptan 
Treatment Component
Subjects will be administered tolvaptan on an age- and weight-based 
scale.  Tolvaptan doses can be titrated QD and will be based on 
serum sodium levels assessed at > 20 hours following initiation of 
therapy and each subsequent dose; titration may not occur within 20 
hours of the previous dose.  Titration is limited to no more than 
twice the previous dose and will be limited to the maximum dose 
per body weight. A change in serum sodium 4 mEq/L (mmol/L) 
from baseline should warrant titration.

Subjects < 2 years of age or weighing < 10 kg are excluded 
until an oral liquid formulation is available.  

Subjects 2 years of age and weighing 10 to < 20 kg will 
be given a 3.75-mg tablet on Day 1 with possible up-
titration to 7.5- and 15-mg tablet doses.

Subjects weighing 20 to 50 kg, inclusive, will be given a 
7.5-mg tablet on Day 1 with possible up-titration to 15- and 
30-mg tablet doses.

Subjects weighing > 50 kg will be given a 15-mg tablet on 
Day 1 with possible up-titration to 30- and 60-mg tablet 
doses. 

Subjects weighing 20 kg and taking moderate inhibitors 
of CYP3A4 will be given a half-dose (3.75 or 7.5 mg, by 
weight).  

Subjects weighing > 50 kg and taking potent inhibitors of 
CYP3A4 will be given a one-quarter dose.

Subjects weighing < 20 kg and who are taking any 
CYP3A4 inhibitors will be excluded until such time that an 
oral liquid formulation is available.
Subjects will have the opportunity to titrate per medical need 
according to the guidelines listed above, targeting a final serum 
sodium concentration between 135 and 140 mEq/L (mmol/L).  The 


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clinician-directed target range is also acceptable. Titration 
guidelines are designed to ideally achieve a change in serum sodium 
concentration of at least 4 to 8 mEq/L (mmol/L) /24 hours but not 
12 mEq/L (mmol/L)/24 hours.
Section 3.2.2 
Duration of 
Optional 
Tolvaptan 
Treatment
Section 3.2.3 Fluid Restriction
The option of initiating fluid restriction (all fluids) to 1 liter/day for 
subjects with serum sodium < 130 mmol/L is available at the 
investigator’s discretion.  Fluid restriction should be withheld for at 
least the first 24 hours after tolvaptan administration in order to 
determine the rate and magnitude of serum sodium change.  A 
supplemental serum sodium assessment is scheduled 8 hours 
following the first dose to provide additional information which 
may be used to guide the decision to initiate fluid restriction.
Section 3.2.2 Duration of Optional Tolvaptan Treatment
Subjects will receive daily doses of oral tolvaptan based on 
individual titration results and clinical need.  Treatment can 
continue per clinical need as determined by the investigator in 
consultation with the medical monitor and follow-up visits for 
safety and serum sodium assessments can be adjusted per the 
guidelines in Section 3.2.1.2.  Initiation of tolvaptan treatment can 
be repeated per the individual subject’s need.  If subjects are off 
tolvaptan treatment for > 72 hours, reinitiation of treatment will 
require reassessment of the eligibility criteria and must occur in a 
hospital setting.
For subjects who require long-term treatment, each subject will be 
required to temporarily discontinue treatment at 30 days after the 
start of tolvaptan and be evaluated for continued need for tolvaptan 
treatment.
For subjects who discontinue treatment, if the subject’s serum 
sodium values decrease to unacceptably low levels (per the 
investigator’s judgement) during treatment discontinuation, the 
subject can reinitiate treatment with tolvaptan. If treatment is 
reinitiated within 72 hours after administration of the last dose of 
tolvaptan, subjects will not be required to reinitiate titration a 
hospital setting if they resume treatment at the same dose or a lower 
dose.  If treatment is reinitiated > 72 hours after administration of 
the last dose of tolvaptan, subjects will be required to reinitiate 
titration in a hospital setting.  A dosing schedule for subjects is 
presented in Error! Reference source not found.. 
....
Any subject enrolled in the core safety follow-up component who 
has a medical need for tolvaptan per the investigator’s assessment, 


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may have short-term treatment (ie, a few days of treatment needed 
per episode of hyponatremia) or long-term treatment (ie, treatment 
for weeks to months with concomitant medication). The need for 
treatment beyond 30 days will be determined by a scheduled 
treatment discontinuation after 30 days.
Tolvaptan dose titration (after the initial dose) should be based on 
changes in serum sodium levels as follows:

If the serum sodium level increases by 
≤4 mEq/L (mmol/L)/24 hours and the subject is still below 
the therapeutic target for serum sodium level 
(135 mEq/L [mmol/L]), then the tolvaptan dose may be 
titrated up to the next scheduled dose appropriate for the 
subject’s body weight. 

If the serum sodium level increases > 4 to 
≤8 mEq/L (mmol/L)/24 hours in response to tolvaptan 
treatment and the serum sodium is ≤ 140 mEq/L (mmol/L), 
then the dose of tolvaptan should remain the same for the 
subsequent day.

If the serum sodium level increases 
> 8 mEq/L (mmol/L)/24 hours or reaches a concentration 
of > 140 mEq/L (mmol/L), then the next dose of tolvaptan 
should not be given and the medical monitor should be 
contacted to consider options (ie, down-titration, tolvaptan 
discontinuation, concomitant medication adjustment, fluid 
supplementation and/or withdrawal).

If serum sodium level increases by ≥ 12 mEq/L (mmol/L) 
in the 24 hour period following dosing, or, at any time after 
dosing, the serum sodium level is 145 mEq/L (mmol/L), 
the next dose of tolvaptan should not be given and the 
medical monitor should be contacted immediately to 
consider options. 


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Table 3.2.2-1 
Optional 
Tolvaptan 
Treatment 
Component: 
Dosing Schedule 
(Tablets)
Table 3.2.1-1 Dosing Schedule
Trial Day
Time
Dose
Dose 1 
(Hour 0)
Immediately after 
baseline
(within 3 1 hours)
3.75, 7.5, or 15 mg (as 
applicable)
Dose 2
24 (4) hours postdose
3.75, 7.5, 15, or 30 mg 
(as applicable)
Doses 3
24 (4) hours postdose
3.75, 7.5, 15, 30, or 
60 mg (as applicable)
Table 3.2.2-1 Optional Tolvaptan Treatment 
Component: Dosing Schedule 
(Tablets)
Dosing 
Time 
Point
Time
Dose
Dose 1 
(Hour 0)
Immediately after 
baseline
(within 2-4 hours)
3.75, 7.5, or 15 mg (as 
applicable)
Dose 2
24 (4) hours post 
previous dose
3.75, 7.5, 15, or 30 mg 
(as applicable)
Doses 
3
24 (4) hours post 
previous dose
3.75, 7.5, 15, 30, or 
60 mg  (as applicable)


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Old Text: Figure 3.2.1-1
Figure 3.2.1-1Titration Scheme


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New Text: Figure 3.2.2-1
Figure 3.2.2-1Titration Scheme


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Section 3.2.3 
Rescue Therapy
Section 3.2.4 Eligibility Criteria for Tolvaptan Treatment
Subjects must meet the eligibility criteria for tolvaptan treatment 
before being administered tolvaptan in each cycle.  It is required to 
have documentation of chronic hyponatremia, defined by serum 
sodium < 130 mmol/L persisting for 48 hours duration and 
assessed at least 12 hours apart.  Finally, there must be a final serum 
sodium assessed STAT prior to the initial dose of tolvaptan.  This 
final serum sodium screening assessment must be verified to be 
< 130 mmol/L prior to the initial dose.  Subjects who do not meet all 
of these requirements are ineligible for tolvaptan administration and 
may rescreen if eligible at a later date.
Table 3.2.4-1 Eligibility Criteria for Tolvaptan 
Treatment
1.
Subjects hospitalized with euvolemic or hypervolemic 
hyponatremia resistant to initial standard background 
therapy (including fluid restriction and excluding a 
vasopressin antagonist) and who are deemed by the 
investigator as likely to benefit from a therapy that raises 
serum sodium levels
2.
Persistent euvolemic or hypervolemic hyponatremia 
defined as being documented as present for at least 
48 hours, evidenced by at least 2 serum sodium 
assessments < 130 mmol/L drawn at least 12 hours apart 
(these values can be documented using historical values 
previously obtained per standard of care); a third (STAT) 
serum sodium assessment < 130 mmol/L, which will serve 
as the baseline value for efficacy endpoints, is to be 
obtained within 3 (1) hours of the first dose of trial 
medication
3.
Ability to take oral medication as tablets
Section 3.2.3 Rescue Therapy
Subjects in either component of the trial who develop worsening 
hyponatremia symptoms may receive rescue therapy.  Rescue 
therapy is defined as any treatment, eg, hypertonic saline, isotonic 
saline (with or without diuretic for the purpose of increasing the 
serum sodium level), plasmapheresis/dialysis, demeclocycline, urea, 
lithium, or commercial vaptans intended to raise the level of serum 
sodium.
A subject requiring rescue therapy at any time during the optional 
tolvaptan treatment component will be discontinued from tolvaptan 
prior to receiving rescue therapy and should continue to be followed 
per the schedule of assessments in the core safety follow-up 
component of the trial.  Treatment may be reinitiated only per 
consultation with the medical monitor. Subjects who have received 
rescue therapy because of inadequate response to tolvaptan will not 
be allowed to reinitiate tolvaptan treatment. 
For subjects in the optional tolvaptan component only, serum 
sodium values drawn up to, but not after, the initiation of rescue 
therapy will be included in the calculation of the efficacy endpoint. 
Additional guidelines for rescue therapy concerning hyponatremia 
symptoms and decreasing serum sodium level are as follows: 

If a subject has worsening symptoms and/or has a serum 
sodium level at or below the baseline value, repeat serum 
sodium [STAT] to confirm level, and begin rescue therapy.

If a subject is asymptomatic and serum sodium has 
decreased by ≥ 4 mEq/L (mmol/L), but is still above the 
baseline value, consider need for rescue therapy. 

If a subject is asymptomatic and serum sodium has 
decreased by ≤ 3 mEq/L (mmol/L), but is still above the 
baseline value, no action is required.


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4
.
Ability to commit to remain abstinent or practice double-
barrier birth control during tolvaptan treatment and for 
14 days following the last dose of IMP for sexually active 
females of childbearing potential
5
.
Ability to maintain adequate fluid intake whether orally or 
via IV support with adequate monitoring
Subjects will be ineligible for tolvaptan treatment if they meet any 
of the following criteria:
Table 3.2.4-2 Ineligibility Criteria for Tolvaptan 
Treatment
1.
Has evidence of hypovolemia or intravascular volume 
depletion (eg, hypotension, clinical evidence of volume 
depletion, response to saline challenge); if the subject has a 
systolic blood pressure < 90 mmHg or pulse > 120 bpm, 
then volume status should be specifically clinically 
assessed to rule out volume depletion
2.
Has serum sodium < 120 mmol/L, with or without 
associated neurologic impairment (ie, symptoms such as 
apathy, confusion, or seizures)
3.
Use of potent CYP3A4 inhibitors in subjects 50 kg or 
moderate CYP3A4 inhibitors in subjects < 20 kg (see 
Section 3.2)
4.
Lacks free access to water or without ICU-level fluid 
monitoring and management
5.
Has a history or current diagnosis of nephrotic syndrome
6.
Has transient hyponatremia likely to resolve (eg, head 
trauma or post-operative state)
7.
Has hyperkalemia defined as serum potassium above the 
ULN for the appropriate pediatric age range


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8.
Has eGFR < 30 mL/min/1.73 m2 calculated by the 
following equation:
eGFR (mL/min/1.73 m2) = 0.413 height (cm)/serum 
creatinine (mg/dL)
9.
Has AKI defined as:
Increase in serum creatinine by 0.3 mg/dL (26.5 
mol/L) within 48 hours; or
Increase in serum creatinine to 1.5 times baseline, which 
is known or presumed to have occurred within the prior 7 
days; or
Urine volume < 0.5 mL/kg/h for 6 hours
10.
Has severe or acute neurological symptoms requiring other 
intervention (eg, hyperemesis, obtundation, seizures)
11.
Has had treatment for hyponatremia with:
Hypertonic saline (including normal saline challenge) 
within 8 hours of qualifying serum sodium assessments;
Urea, lithium, demeclocycline, conivaptan, or tolvaptan 
within 4 days of qualifying serum sodium assessments;
Other treatment for the purpose of increasing serum 
sodium concurrent with dosing of trial medication
12.
Has anuria or urinary outflow obstruction, unless the 
subject is, or can be, catheterized during the trial
13.
Has a history of drug or medication abuse within 3 months 
prior to Pretreatment Baseline or current alcohol abuse
14.
Has a history of hypersensitivity and/or idiosyncratic 
reaction to benzazepine or benzazepine derivatives (such 
as benazepril)
15.
Has psychogenic polydipsia (subjects with other 
psychiatric illness may be included per medical monitor 
approval)
16.
Has uncontrolled diabetes mellitus defined as fasting 
glucose > 300 mg/dL (16.7 mmol/L)
17.
Has screening liver function values > 3 ULN


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18.
Has deficient coagulation (eg, cirrhotic at risk of GI bleed), 
including subjects who meet any of the following criteria:  
a major GI bleed within the past 6 months, evidence of 
active bleeding (eg, epistaxis, petechiae/purpura, 
hematuria, or hematochezia), platelet count < 50,000/L, 
or use of concomitant medications known to increase 
bleeding risk
19.
Has hyponatremia due to the result of any medication that 
can safely be withdrawn (eg, thiazide diuretics)
20.
Has hyponatremia (eg, hyponatremia in the setting of 
adrenal insufficiency, untreated hypothyroidism, or 
hypotonic fluid administration) that is most appropriately 
corrected by alternative therapies
21.
Is currently pregnant or breastfeeding
22.
Has any medical condition that, in the opinion of the 
investigator, could interfere with evaluation of the trial 
objectives or safety of the subjects (eg, Child-Pugh class C 
or NYHA class IV)
23.
Is deemed unsuitable for trial participation in the opinion 
of the investigator
AKI = acute kidney injury; eGFR = estimated glomerular 
filtration rate; ICU = intensive care unit; NYHA = New York 
Heart Association.
Section 3.2.4 
Fluid Restriction
New section in this amendment
Fluid restriction can be a standard of care in both the core safety 
follow-up component and the optional tolvaptan treatment 
component of the trial.
The option of initiating fluid restriction (all fluids) to 1 liter/day 
for tolvaptan-treated subjects with serum sodium < 130 mEq/L 
(mmol/L) is available at the investigator’s discretion.  Fluid 
restriction must not be initiated for at least the first 24 hours after 
tolvaptan administration in order to determine the rate and 
magnitude of serum sodium change.  A supplemental serum sodium 
assessment is scheduled 8 hours following the first dose of tolvaptan 
to provide additional information which may be used to guide the 


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decision to initiate fluid restriction in the future.  
Section 3.3 Trial 
Population
Up to 140 male and female subjects may be eligible for this trial.  
All subjects will have enrolled in at least one of the previous 
tolvaptan pediatric hyponatremia trials (ie, 156-08-276, 156-12-205, 
or 156-13-207).  The trial will be conducted at up to 65 centers 
globally.
No text in this section.
Section 3.3.1
Core Safety 
Follow-up 
Component
Section 3.3.1 Trial Population for Tolvaptan Treatment
Subjects with euvolemic or hypervolemic hyponatremia 
(< 130 mmol/L) that persists despite initial standard background 
therapy (including fluid restriction and excluding a vasopressin 
antagonist) may be eligible to be screened for treatment with 
tolvaptan. These subjects include, but are not limited to, those 
diagnosed and admitted to a hospital for treatment of heart failure, 
hepatocellular disease (including cirrhosis), or SIADH.  Subjects 
with acute hyponatremia or hyponatremia expected to resolve 
spontaneously will be ineligible for tolvaptan treatment.  Children 
with an impaired ability to sense or communicate their thirst will 
either be required per protocol to undergo closer in hospital 
observation, laboratory and urine output monitoring, or will be 
ineligible for tolvaptan treatment if this is not possible.  Children 
with hypovolemic hyponatremia or those who are at risk of such, 
secondary to any underlying conditions that cause volume depletion, 
are ineligible for tolvaptan treatment.
Children with Factor V Leiden or Factor VII abnormalities may be 
eligible for treatment only if the benefit is judged to outweigh any 
risk.  Children with hepatocellular disease (including cirrhosis) who 
have platelet counts between 50,000 and 100,000/L may be 
administered IMP if the need to treat is felt to outweigh the 
increased risk of GI bleeding.
Children can develop symptomatic hyponatremia more frequently 
than adults and at less severe levels of hyponatremia due to the large 
brain volumes in relatively small skulls.  The most serious 
consequence of hyponatremia is hyponatremic encephalopathy, 
Section 3.3.1 Core Safety Follow-up Component
Up to 140 male or female subjects may be eligible for this trial.  All 
subjects will have participated in one of the previous tolvaptan 
pediatric hyponatremia trials (156-08-276, 156-13-207, or 
156-12-205).  All subjects will be observed for post-treatment safety 
for at least 6 months. Subjects enrolled in the core safety follow-up 
component may enter the optional tolvaptan treatment component of 
the trial at any time during the conduct of the trial based on clinical 
need and the investigator’s discretion.


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which occurs in over 50% of children with serum sodium < 125 
mmol/L.17  Hospitalized hyponatremic encephalopathy is seen in 
association with SIADH or in the post-operative period.  
Hyponatremic encephalopathy is a medical emergency that requires 
immediate intervention; thus, subjects with known risk factors for 
developing hyponatremic encephalopathy will be ineligible for 
tolvaptan treatment (ie, hypoxia, infection, brain injury, 
neurosurgery, seizure disorders, cerebritis, encephalopathy, central 
nervous system disorders such as cytotoxic and vasogenic cerebral 
edema, space-occupying brain lesion, or elevated AVP levels).18  
Symptoms include headache, nausea and vomiting, weakness, 
confusion, altered consciousness, and lethargy and may progress to 
more advanced symptoms, including seizures, coma, and death, if 
untreated.  Subjects with overt symptoms of hyponatremia that 
require immediate intervention to raise serum sodium acutely will 
be ineligible for tolvaptan treatment; this syndrome is rapidly 
reversible with hypertonic saline administration.
Additionally, those subjects who are at risk of developing cerebral 
demyelination will be ineligible for tolvaptan treatment, including 
subjects who have severe hyponatremia 120 mmol/L, 
hypernatremia, hypoxemia, severe liver disease, alcoholism, severe 
burns, severe malnutrition, hypokalemia, diabetes, or renal 
failure.17,18,19,20
Subjects eligible for treatment with tolvaptan will be initially 
identified based on serum sodium concentrations that persist at 
levels < 130 mmol/L despite initial standard background therapy 
(including fluid restriction and excluding a vasopressin antagonist).  
Upon determination of eligibility, each subject’s serum sodium will 
be reassessed just before tolvaptan administration to confirm it 
remains persistent below this threshold prior to intended treatment 
initiation.
If any result, during the Pretreatment Baseline period for tolvaptan 
treatment is 130 mmol/L, the subject will be ineligible for 
tolvaptan administration at that time.  Subjects may be rescreened 


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for treatment, as appropriate.
Section 3.3.1.1 
Tolvaptan 
Administration 
by Hyponatremia 
Etiology
Investigators should assess subjects’ appropriateness to receive 
tolvaptan.  Each investigator should ultimately use his/her medical 
judgment to make the final determination.  The guidelines listed in 
Table 3.3.1.1-1 are to help guide the medical judgment of each 
investigator.
Table 3.3.1.1-1
Screening Algorithms by 
Hyponatremia Etiology
SIADH/Other
CHF
Hepatocellular 
Disease
Two serum sodium 
assessments of < 
130 mmol/L at 
least 12 hours 
apart
Two serum sodium 
assessments of < 
130 mmol/L at 
least 12 hours 
apart
Two serum sodium 
assessments of < 
130 mmol/L at 
least 12 hours 
apart
One serum sodium 
assessment 3 (1) 
hours before 
tolvaptan 
administration of < 
130 mmol/L
One serum sodium 
assessment 3 (1) 
hours before 
tolvaptan 
administration of < 
130 mmol/L
One serum sodium 
assessment 3 (1) 
hours before 
tolvaptan 
administration of < 
130 mmol/L
Screen subjects per 
AKI criteria per 
treatment 
eligibility criteria
Screen subjects per 
AKI criteria per 
treatment 
eligibility criteria
Screen subjects per 
AKI criteria per 
treatment 
eligibility criteria
Collect labsa
Collect labsa
Collect labsa
Calculate serum 
osmolality, FENa, 
and FE urate as 
appropriate
Calculate serum 
osmolality, FENa, 
and FE urate as 
appropriate
Calculate serum 
osmolality, FENa, 
and FE urate as 
appropriate
Cardiologist 
documented 
diagnosis of CHF
This section was removed in this amendment.


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Discontinue or 
stabilize diuretic 
use prior to 
tolvaptan 
administration
AKI = acute kidney injury.
aRefer to Table 3.7-2 and Table 3.7.3.2.1-1 for a complete list of 
laboratory assessments.
Section 3.3.1.2 
Hyponatremia 
due to Syndrome 
of Inappropriate 
Secretion of 
Antidiuretic 
Hormone
Evidence of low serum sodium should be demonstrated for at least 
48 hours prior to scheduled tolvaptan administration.  Two serum 
sodium assessments of < 130 mmol/L should be collected at least 
12 hours apart.  One serum sodium assessment of < 130 mmol/L 
should be collected 3 (1) hours before the initial tolvaptan 
administration.  If any result, during the Pretreatment Baseline 
period is 130 mmol/L, the subject will be ineligible for treatment 
with tolvaptan.  Subjects may be rescreened, as appropriate.  Urine 
chemistry should be assessed and the serum osmolality, FENa, and 
FE urate should be calculated as appropriate for all subjects prior to 
the first dose of tolvaptan.  Please see Table 3.7-2 for a full schedule 
of assessments and timing.
Subjects must be screened per the acute kidney injury (AKI) criteria 
detailed in the treatment eligibility criteria (Section 3.2.4).
This section was removed in this amendment.
Section 3.3.1.3 
Hyponatremia 
due to 
Congestive Heart 
Failure
Evidence of low serum sodium should be demonstrated for at least 
48 hours prior to scheduled tolvaptan administration.  Two serum 
sodium assessments of < 130 mmol/L should be collected at least 
12 hours apart.  One serum sodium assessment of < 130 mmol/L 
should be collected 3 (1) hours before the initial tolvaptan 
administration.  If any result, during the Pretreatment Baseline 
period is 130 mmol/L, the subject will be ineligible for treatment 
with tolvaptan.  Subjects may be rescreened, as appropriate.  Urine 
chemistry should be assessed and the serum osmolality, FENa, and 
FE urate should be calculated as appropriate for all subjects prior to 
the first dose of tolvaptan.  Please see Table 3.7-2 for a full schedule 
of assessments and timing.
This section was removed in this amendment.


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Loop diuretic use should be assessed and minimized where possible.  
Steady doses of diuretics are acceptable.  Thiazide diuretics must be 
stopped before tolvaptan administration; the time that these 
medications must be stopped prior to the first tolvaptan dose 
depends on the half-life of the diuretic.  The medical monitor should 
be contacted if there are questions.
A definitive diagnosis of CHF by a cardiologist must be 
documented.
Subjects must be screened per the AKI criteria detailed in the 
treatment eligibility criteria (Section 3.2.4).
Section 3.3.1.4 
Hyponatremia 
due to 
Hepatocellular 
Disease
Evidence of low serum sodium should be demonstrated for at least 
48 hours prior to scheduled tolvaptan administration.  Two serum 
sodium assessments of < 130 mmol/L should be collected at least 12 
hours apart.  One serum sodium assessment of < 130 mmol/L 
should be collected 3 (1) hours before the initial tolvaptan 
administration.  If any result, during the Pretreatment Baseline 
period is 130 mmol/L, the subject will be ineligible for treatment 
with tolvaptan.  Subjects may be rescreened, as appropriate.  Urine 
chemistry should be assessed and the serum osmolality, FENa, and 
FE urate should be calculated as appropriate for all subjects prior to 
the first dose of tolvaptan.  Please see Table 3.7-2 for a full schedule 
of assessments and timing.
Subjects must be screened per the AKI criteria detailed in the 
treatment eligibility criteria (Section 3.2.4).
The underlying etiology of hepatocellular disease must be 
documented.
This section was removed in this amendment.
Section 3.3.2
Optional 
Tolvaptan 
Treatment 
Component
New section in this amendment
Subjects enrolled in the Core Safety Follow-up Component of the 
trial may be eligible for treatment with tolvaptan.  These subjects 
include, but are not limited to, those diagnosed and admitted to a 
hospital for treatment of heart failure, hepatocellular disease 
(including cirrhosis), or SIADH/other.  Subjects with acute 


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hyponatremia or hyponatremia expected to resolve spontaneously 
will be ineligible for tolvaptan treatment.  Children with an impaired 
ability to sense or communicate their thirst will either be required 
per protocol to undergo closer in hospital observation, laboratory 
and urine output monitoring, or will be ineligible for tolvaptan 
treatment if this is not possible.  Children with hypovolemic 
hyponatremia or those who are at risk of such, secondary to any 
underlying conditions that cause volume depletion, are ineligible for 
tolvaptan treatment.
Section 3.3.2.1 
Hyponatremia 
Etiology in 
Children and 
Adolescents
New section in this amendment
Children with Factor V Leiden or Factor VII abnormalities may be 
eligible for treatment only if the benefit is judged to outweigh any 
risk.  Tolvaptan may be administered to children with hepatocellular 
disease (including cirrhosis) who have platelet counts between 
50,000 and 100,000/L if the need to treat is felt to outweigh the 
increased risk of GI bleeding.
Children can develop symptomatic hyponatremia more frequently 
than adults and at less severe levels of hyponatremia because of the 
large brain volumes in relatively small skulls.  The most serious 
consequence of hyponatremia is hyponatremic encephalopathy, 
which occurs in over 50% of children with serum sodium 
< 125 mmol/L.17  Hyponatremic encephalopathy is seen in 
hospitalized children and adolescents in association with SIADH or 
in the post-operative period.  Hyponatremic encephalopathy is a 
medical emergency that requires immediate intervention; thus, 
subjects with known risk factors for developing hyponatremic 
encephalopathy will be ineligible for tolvaptan treatment (ie, 
hypoxia, infection, brain injury, neurosurgery, seizure disorders, 
cerebritis, encephalopathy, central nervous system disorders such as 
cytotoxic and vasogenic cerebral edema, space-occupying brain 
lesion, or elevated AVP levels).18  Symptoms include headache, 
nausea and vomiting, weakness, confusion, altered consciousness, 
and lethargy and may progress to more advanced symptoms, 
including seizures, coma, and death, if untreated.  Subjects with 
overt symptoms of hyponatremia that require immediate 
intervention to raise serum sodium acutely will be ineligible for 


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tolvaptan treatment; this syndrome is rapidly reversible with 
hypertonic saline administration.
Additionally, those subjects who are at risk of developing cerebral 
demyelination will be ineligible for tolvaptan treatment, including 
subjects who have severe hyponatremia 120 mEq/L (mmol/L), 
hypernatremia, hypoxemia, severe liver disease, alcoholism, severe 
burns, severe malnutrition, hypokalemia, diabetes, or renal 
failure.17,18,19,20
Subjects eligible for treatment with tolvaptan will be identified 
based on serum sodium concentrations that persist at levels 
< 130 mEq/L (mmol/L). Upon determination of eligibility, each 
subject’s serum sodium will be reassessed just before tolvaptan 
administration to confirm it remains below this threshold prior to 
intended treatment initiation.
If any serum sodium value obtained during the pretreatment 
baseline period for tolvaptan treatment is 130 mEq/L (mmol/L), 
the subject will be ineligible for tolvaptan administration at that 
time.  Subjects may be rescreened for treatment, as appropriate.
Section 3.4.1
Informed 
Consent
Written informed consent or patient information sheet (PIS) and 
assent as appropriate will be obtained from the subject’s parent or 
legal guardian, in accordance with requirements of the trial center’s 
institutional review board/independent ethics committee (IRB/IEC).  
The subject, as required by the trial center’s IRB/IEC, must provide 
informed assent at Baseline and as such must be able to understand 
that he or she can withdraw from the trial at any time.  Age 
appropriate assent documents will be created and subjects who are 
able will be required to reconsent or assent as appropriate if they 
matriculate from one age group to another.  Subjects who become 
legal adults prior to the end of the trial will be required to provide 
written informed consent at that time.
...
Written informed consent or patient information sheet (PIS) and 
assent as appropriate will be obtained from the subject’s parent or 
legal guardian, in accordance with requirements of the trial center’s 
institutional review board/independent ethics committee (IRB/IEC).  
The subject, as required by the trial center’s IRB/IEC, must provide 
informed assent at baseline (which may be the final visit in the 
previous titrated oral IMP trial) and as such must be able to 
understand that he or she can withdraw from the trial at any time.  
Age appropriate assent documents will be created and subjects who 
are able will be required to reconsent or assent as appropriate if they 
matriculate from one age group to another.  Subjects who became 
legal adults during the previous trial of titrated oral IMP (tolvaptan 
in Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 
156-12-205) or who become legal adults during this trial will be 
required to provide written informed consent as soon as they reach 


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legal age.
...
Section 3.4.2 
Inclusion Criteria
Eligible subjects must satisfy all informed consent requirements, as 
well as meet all the following inclusion criteria:
Subjects invited to participate in the core safety follow-up 
component of the trial must satisfy all informed consent 
requirements, as well as meet all the following inclusion criteria:
...
For initiation or reinitiation of tolvaptan treatment in the Optional 
Tolvaptan Treatment Component of the trial additional criteria 
apply as outlined in Appendix 5.
Table 3.4.2-1 
Inclusion Criteria 
for Core Safety 
Follow-up 
Component
Table 3.4.2-1 Inclusion Criteria for All Subjects
1.
Enrollment in at least one of the previous tolvaptan 
pediatric trials for hyponatremia (ie, Trial 156-08-276, 156-
12-205, or 156-13-207)
2.
Trial-specific written informed consent/assent obtained 
from a parent/guardian or legally acceptable representative, 
as applicable for local laws, prior to the initiation of any 
protocol-required procedures.  In addition, the subject must 
provide informed assent at Baseline and must be able to 
understand that he or she can withdraw from the trial at any 
time.  All informed consent/assent procedures must be in 
accordance with the trial center’s IRB/IEC and local 
regulatory requirements.
3.
Ability to comply with all requirements of the trial
4.
Willing to be clinically followed for 6 months
Table 3.4.2-1 Inclusion Criteria for Core Safety 
Follow-up Component
1.
Enrollment in one of the previous tolvaptan pediatric trials 
for hyponatremia (ie, Trial 156-08-276, 156-13-207, or 
156-12-205)
2.
Trial-specific written informed consent/assent obtained 
from a parent/guardian or legally acceptable representative, 
as applicable for local laws, prior to the initiation of any 
protocol-required procedures.  In addition, the subject must 
provide informed assent at baseline and must be able to 
understand that he or she can withdraw from the trial at any 
time.  All informed consent/assent procedures must be in 
accordance with the trial center’s IRB/IEC and local 
regulatory requirements.
3.
Ability to comply with all requirements of the trial
4.
Willingness to be clinically followed for 6 months
Section 3.4.3
Exclusion 
Criteria
There are no exclusion criteria for entry into this trial.
There are no exclusion criteria for entry into the safety follow-up 
component of this trial.
For initiation or reinitiation of tolvaptan treatment in the Optional 
Tolvaptan Treatment Component of the trial additional criteria 
apply as outlined in Appendix 5.
Section 3.5.1
Primary 
Section 3.5.1.1 Safety Variables
Section 3.5.1 Primary Outcome Variables


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Outcome 
Variables
The primary safety variables include the following:

AEs, including cases of dehydration

Vital signs

Body weight, height, and growth percentiles

Tanner Stages
Data for the primary efficacy variable will be collected for all 
subjects receiving tolvaptan in the Optional Tolvaptan Treatment 
Component of the trial and will be summarized as follows:

Change from baseline in serum sodium while tolvaptan is 
being administered 
Section 3.5.1.1.1 
Safety Variables 
for Tolvaptan 
Treatment
In addition to the safety variables reported for all subjects, the 
following variables will be assessed for subjects on tolvaptan:

Percentage of subjects with overly rapid improvement in 
serum sodium (12 mmol/L in 24 hours after the first dose 
at introduction or reintroduction of IMP)

Percentage of subjects who experience recurrence of 
hyponatremia while on IMP

Clinical laboratory abnormalities:

Serum sodium, overly rapid changes in serum sodium

Changes from baseline in ALT and AST
This section was removed in this amendment
Section 3.5.2.1 
Efficacy 
Variables
Section 3.5.2.1 Efficacy Variables for Tolvaptan Treatment
The secondary efficacy endpoint is the change in serum sodium 
from baseline at each visit while the IMP is being administered.
Serum sodium will be assessed daily during titration.  Then, it will 
be assessed at each visit, at a minimum monthly once a subject has 
reached the optimal dose.
Section 3.5.2.1 Efficacy Variables
Data for the secondary efficacy variables will be collected for all 
subjects receiving tolvaptan in the Optional Tolvaptan Treatment 
Component of the trial and will be summarized as follows:

Percentage of subjects who require rescue therapy while on 
tolvaptan

Percentage of subjects requiring continuation of tolvaptan 
following 30 days of treatment
Additionally, for all subjects enrolled in the Core Safety Follow-up 
Component of the trial the following variable will be assessed and 
summarized:

Change from baseline in QoL assessments


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Section 3.5.2.2
Safety Variables
Section 3.5.2.2 Pharmacokinetic Variables for Tolvaptan 
Treatment
The PK endpoints are the plasma concentrations of tolvaptan and 
metabolites in subjects who have continued tolvaptan therapy for 
8 consecutive weeks.
Section 3.5.2.2 Safety Variables
Data for the secondary safety variables will be collected for all 
subjects enrolled in the Core Safety Follow-up Component of the 
trial.  Safety variables listed below and their differences from 
baseline will be summarized.
The primary safety variables are the following:

AE reporting

Growth percentiles for body height and body weight

Tanner Staging

Change from baseline in serum sodium concentration
In addition to the safety variables reported for all subjects, the 
following variables will be assessed for subjects who enter the 
Optional Tolvaptan Treatment Component of the trial:

Percentage of subjects with overly rapid correction in 
serum sodium (12 mEq/L ([mmol/L]) in 24 hours after 
the first dose at introduction or reintroduction of tolvaptan)

Changes from baseline in ALT, AST, and BT.
Section 3.5.2.3
Pharmacokinetic 
Variable: 
Optional 
Tolvaptan 
Treatment 
Component
No text in this section
Section 3.5.2.3 Pharmacokinetic Variable: Optional Tolvaptan 
Treatment Component
The PK endpoints are the plasma concentrations of tolvaptan and 
metabolites in subjects who have continued tolvaptan therapy for 
8 consecutive weeks, ignoring short interruptions to assess need for 
continued therapy.
Section 3.5.3 
Exploratory 
Variables
No text in this section.
Exploratory endpoints will include changes from baseline for the 
neurocognition test battery assessments..
Section 3.5.3.1 
Exploratory endpoints will include Quality of Life assessments.
This section was removed in this amendment


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Safety Variables
Section 3.6
Measures to 
Minimize/Avoid 
Bias
This is an observational trial with an option for open-label 
treatment.  Subjects will only be dosed based on clinical need and 
the investigator’s discretion.  The dose of the IMP assigned to an 
eligible subject is determined by the subject’s age, weight, and the 
use of CYP3A4 inhibitors.
No measures to minimize bias were implemented as this is an 
observational trial with an option for open-label treatment. Subjects 
will only be dosed based on clinical need and the investigator’s 
discretion. The dose of the IMP assigned to an eligible subject is 
determined by the subject’s age, weight, and the use of CYP3A4 
inhibitors.
Section 3.7 Trial
Procedures
Parents or legal guardians will consent and subjects will assent (as 
applicable) at Baseline.  Enrollment in this trial should directly 
follow completion or discontinuation of the previous trial (ie, 
156-08-276, 156-12-205, or 156-13-207).  The end of trial visit in 
the previous trial will serve as the Baseline Visit in this trial.  
Subjects will be followed monthly for 6 months, alternating between 
telephone calls and in-clinic visits, to clinically evaluate children 
and adolescent subjects with hyponatremia, regardless of the need 
for treatment.  If a subject has a clinical need for tolvaptan, the 
subject may be screened for eligibility to be dosed with tolvaptan.  
The subject must have been off of treatment with IMP for a 
minimum of 7 days following the end of treatment in the previous 
trial to assess the subject’s clinical need for treatment with 
tolvaptan.
After enrollment in the trial, if subjects are to initiate tolvaptan 
treatment, screening for eligibility must occur −4 to −1 days prior to 
each dosing cycle.  Eligible subjects will receive oral tolvaptan once 
daily based on clinical need as determined by the investigator in 
consultation with the sponsor’s medical monitor.  Subjects who 
meet the eligibility criteria for tolvaptan treatment will initially be 
administered a 3.75-, 7.5-, or 15-mg dose based on age, weight, and 
the use of CYP3A4 inhibitors on Day 1 of the cycle.  Trial treatment 
should begin and be titrated in a hospital setting.  Dosing of 
tolvaptan should occur in the morning.  After titration is completed 
and the dose has stabilized in-hospital, subjects should return to the 
clinical site for assessment of serum sodium concentrations on an 
ongoing basis to monitor the stability of their hyponatremia or their 
achievement of normal or clinician-directed target range serum 
No text in this section


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sodium per the guidelines in Section 3.1.1.1.  Treatment can be 
discontinued and cycles may be repeated as needed per individual 
subject’s need (eg, during chemotherapy treatments).  If subjects are 
off of tolvaptan treatment for 48 hours, reinitiation of treatment 
will require reassessment of eligibility criteria and should begin in a 
hospital setting.  Tolvaptan should be titrated with regular serum 
sodium assessments.  After discontinuation of tolvaptan, serum 
sodium concentrations will be assessed at 48 (4) hours and 7 (+ 1) 
days post-last dose.
Trial assessment time points are summarized in Table 3.7.1.  
Assessment time points for tolvaptan treatment are summarized in 
Table 3.7-2.
Section 3.7.1
Core Safety 
Follow-up 
Component
New section in this amendment
Parents or legal guardians will consent and subjects will assent (as 
applicable) at baseline.  Participation in this trial should directly 
follow completion or discontinuation of the previous trial of titrated 
oral IMP (tolvaptan in Trial 156-08-276, tolvaptan or placebo in 
Trials 156-13-207 and 156-12-205).  The final laboratory 
assessments from the previous trial of titrated oral IMP will serve as 
the baseline laboratory assessments for this trial. Subjects will be 
followed monthly for 6 months, alternating between telephone calls 
and clinical trial site visits, to clinically evaluate children and 
adolescent subjects with dilutional (euvolemic or hypervolemic) 
hyponatremia, regardless of the need for treatment.  
Trial assessments and time points for the Core Safety Follow-up 
Component are summarized in Table 3.7.1-1 and described in 
Section 3.7.3.1.  


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Old Text:  Table 3.7-1
Schedule of Assessments for All Subjects
Table 3.7-1
Schedule of Assessments for All Subjects
Procedures
Baseline Visita
Day 1
Months 1, 3, and 5 (2 weeks)
Telephone Contactb
Months 2, 4, and 6 (2 weeks)/ET
In-clinic Assessments
Informed consent and assent
X
Review inclusion criteria
X
Demographic information
X
Medical and hyponatremia history
X
Serum chemistryc
X
ALT and AST only:  Month 2
Vital signsd
X
X
Directed physical examination
X
X
Body height and weight
X
X
Tanner Staginge
X
Month 6
Quality of Life
X
X
Concomitant medications
<---------------------------------------------------------------------------------------------------------------------------------------->
Adverse events
<---------------------------------------------------------------------------------------------------------------------------------------->
ET = early termination.
aThe last visit of the previous trial will serve as the Baseline Visit.  All assessments can be carried over to this trial.
bTelephone contacts can be replaced with in-clinic visits.
cAll ALT and AST tests should have a reflexive total bilirubin if the ALT, AST, or both values are >3 ULN.
dVital signs to be assessed include supine blood pressure, heart rate, respiratory rate, and temperature.  Vital signs should be assessed prior to any blood draws 
per protocol.
eThe collection of Tanner Staging data is required at the Month 6 in-clinic visit and every attempt should be made to collect this information.  Tanner Staging 
must be completed together with the physical examination by the same trial-affiliated clinician in the most inconspicuous manner for the subject as 
possible.  Tanner Staging could be completed by the trial-affiliated pediatrician or family practitioner (additionally physician’s assistant or nurse 
practitioner in the US).  A subject who reaches Stage 5 (both in pubic hair and genitalia) does not need to continue with Tanner Staging.  Sites should make 
attempts to have examiners of both gender types.  Attempts should be made to have the examination performed by the same gender as the subject.  
Otherwise, trial-affiliated personnel of the same gender as the subject (ie, nurse) should be in the same examination room as the subject.


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New Text:  Table 3.7.1-1
Core Safety Follow-up Component: Schedule of Assessments for All Subjects
Table 3.7.1-1 Core Safety Follow-up Component: Schedule of Assessments for All Subjects
Procedures
Baselinea
Month 1
(+2 Weeks)
Month 2
(+2 Weeks)
Month 3
(+2 Weeks)
Month 4
(+2 Weeks)
Month 5
(+2 Weeks)
Month 6 or Early 
Termination
(+2 Weeks)
Informed consent and assent
X
Review inclusion criteria
X
Demographic information
X
Telephone assessmentb
X
X
X
In-clinic assessment
X
X
X
X
Medical and hyponatremia history
X
X
X
X
Vital signsc
X
X
X
X
Directed physical examination
X
X
X
X
Body height/weight/ growth percentiles
X
X
X
X
Tanner Staging
X
X
X
X
Serum sodium 
X
X
X
X
Assess ALT, AST, and BT
X
X
X
X
Neurocognitive Assessmentd
X
X
X
X
Quality of Life
X
X
X
X
Concomitant medications
Adverse events
aThe final laboratory assessments from the previous trial (tolvaptan in Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 156-12-205) can serve 
as the baseline laboratory assessments for this trial.  All assessments, with the exception of the neurocognitive assessment, can be carried over from 
previous trial of titrated oral IMP to this trial, if possible.  Body height, body weight, Tanner Staging and baseline laboratory assessments can be carried 
forward from the last visit in the previous trial if done within one month, but all other assessments must be completed at the baseline visit and all including 
height, Tanner Staging and laboratory assessments must be re-done if more than one month passes between trials.
bTelephone calls can be replaced with clinical site visits.
cVital signs to be assessed include supine blood pressure, heart rate, respiratory rate, and temperature.  Vital signs should be assessed prior to any blood 
draws.
dNeurocognitive assessment will be performed at baseline and at Months 2, 4, and 6, and should be done within 1 hour of blood draws for serum sodium 
assessment. 


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Old Text:  Table 3.7-1
Schedule of Assessments for Tolvaptan Treatment
Table 3.7-2
Schedule of Assessments for Tolvaptan Treatment
Procedures
Pretreatment Baseline 
Visita,b
Days −4 to −1
Treatment Cycle
Follow-up Period
Titration Period
Maintenance Periodc
Initial 
Follow-up 
(48 4 hours 
post-last 
dose)
7-day 
Follow-up 
(7 + 1 days 
post-last 
dose)
Review eligibility criteria for
  treatment
X
Medical and hyponatremia
  history
X
Urine pregnancy testd
X
Each visit
X
ALT and ASTe
X
Every month (2 days)
X
Serum sodiumf
Within 48 hours prior to 
tolvaptan administration:  
2 assessments at least 
12 hours apart
Day 1:  Baseline (predose, within 
3 [1] hours of dosing), 8 hours 
post-first dose
Day 2 and during Titration 
Period:  24 (4) hours 
post-previous dose
Each visit
(Months 1 to 3: every 
2 weeks [2 days]
Months 4:  every month 
[2 days])
X
X
Directed physical 
  examination
X
Tanner Stagingg
Every 6 months
Tolvaptan dosingh
Once daily
Dispense IMP
End of the Titration Period
X
IMP collection/reconciliation
X
X
PK sample collection
1 sample after 8 consecutive 
weeks of dosing to be 
repeated upon reinitiation of 
therapy for 8 consecutive 
weeks
Concomitant medications
<------------------------------------------------------------------------------------------------------------------------------------------------>


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Table 3.7-2
Schedule of Assessments for Tolvaptan Treatment
Procedures
Pretreatment Baseline 
Visita,b
Days −4 to −1
Treatment Cycle
Follow-up Period
Titration Period
Maintenance Periodc
Initial 
Follow-up 
(48 4 hours 
post-last 
dose)
7-day 
Follow-up 
(7 + 1 days 
post-last 
dose)
Adverse events
<------------------------------------------------------------------------------------------------------------------------------------------------>
aAssessments for the Pretreatment Baseline Visit of the first cycle can be carried over from the previous trial.
bCycles can be repeated per clinical need.  If a subject is off of tolvaptan treatment for 48 hours, reinitiation of treatment will require reassessment of 
eligibility criteria and should begin in a hospital setting.
cVisits for each cycle will occur minimally every 2 weeks (2 days) during Months 1 to 3, and monthly (2 days) from Month 4 onward.
dIf applicable.  Urine pregnancy tests will be performed on female subjects 12 years of age and female subjects < 12 years of age if menstruation has started.
eAll ALT and AST tests should have a reflexive total bilirubin if the ALT, AST, or both values are >3 ULN.
fWithin 48 hours prior to tolvaptan administration, 2 serum sodium assessments must be collected at least 12 hours apart.  Baseline serum sodium testing can 
be waived if baseline is within 48 hours of the last dose administered or as past standard of care within 48 hours prior to tolvaptan administration.
gThe collection of Tanner Staging data is required every 6 months and every attempt should be made to collect this information.  Tanner Staging must be 
completed together with the physical examination by the same trial-affiliated clinician in the most inconspicuous manner for the subject as possible.  
Tanner Staging could be completed by the trial-affiliated pediatrician or family practitioner (additionally physician’s assistant or nurse practitioner in the 
US).  A subject who reaches Stage 5 (both in pubic hair and genitalia) does not need to continue with Tanner Staging.  Sites should make attempts to have 
examiners of both gender types.  Attempts should be made to have the examination performed by the same gender as the subject.  Otherwise, trial-affiliated 
personnel of the same gender as the subject (ie, nurse) should be in the same examination room as the subject.
hThe dose will be titrated at a minimum of 24-hour intervals (4 hours) from 3.75 to 7.5 to 15 mg for subjects 2 years of age and weighing 10 to < 20 kg, 
from 7.5 to 15 to 30 mg for subjects weighing 20 to 50 kg, inclusive, or from 15 to 30 to 60 mg for subjects weighing > 50 kg.  Subjects starting at lower 
doses may be sequentially titrated to the maximal dose allowed for their weight group.
New Text:  Table Removed in this amendment


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Section 3.7.2
Optional 
Tolvaptan 
Treatment 
Component
New section in this amendment
If a subject has a clinical need for tolvaptan, the subject may be 
screened for eligibility to be dosed with tolvaptan.  To assess the 
subject’s clinical need for tolvaptan, the subject must have been off 
treatment with IMP for 7 days following the end of treatment in the 
previous trial of titrated oral IMP (tolvaptan in Trial 156-08-276, 
tolvaptan or placebo in Trials 156-13-207 and 156-12-205).
Eligible subjects will receive oral tolvaptan QD based on clinical 
need as determined by the investigator.  Subjects who meet the 
eligibility criteria for tolvaptan treatment will initially be 
administered a 3.75-, 7.5-, or 15-mg dose based on age, weight, and 
the use of CYP3A4 inhibitors on Day 1 of the cycle.  
Trial treatment will begin and be titrated in a hospital setting.  
Dosing of tolvaptan should occur in the morning.  After titration is 
completed and the dose has stabilized, subjects should return to the 
clinical trial site for assessment of serum sodium concentrations on 
an ongoing basis to monitor the stability of their hyponatremia or 
their achievement of normal or clinician-directed target range serum 
sodium per the guidelines in Section 3.2.1.2.  Treatment can be 
discontinued and cycles may be repeated as needed per individual 
subject’s need (eg, during chemotherapy treatments).  If subjects are 
off tolvaptan treatment for > 72 hours, reinitiation of treatment, 
starting with titration, will require reassessment of the eligibility 
criteria, and titration will begin in a hospital setting.  Tolvaptan 
should be titrated with regular serum sodium assessments.  After 
discontinuation of tolvaptan, serum sodium concentrations will be 
assessed at the clinical trial site at 24 (4) hours and at 7 (1) days 
post-last dose. After the last follow-up visit, all subjects off 
tolvaptan treatment will be contacted for follow-up (AEs and 
concomitant medications) every 3 months.
Trial assessments and time points for the Optional Tolvaptan 
Treatment Component are summarized in Table 3.7.2-1 and 
described in Section 3.7.3.2


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Old Text:  New table in this amendment
New Text: Table 3.7.2-1
Schedule of Assessments for Each Treatment Cycle
Table 3.7.2-3 Schedule of Assessments for Each Treatment Cycle
Proceduresa
Pre-
treatment 
Baselineb
Titration Phaseb
Post-titration
Treatment 
Cycle 
Month 2
Treatment Cycle 
Month 3+
(Maintenance)
Follow- up Phase
Days 
-4 to -1
Day 
1
Day 
2 
and 
3
Day 
4
Day 
7, 14 
and 
21
Day 
30 
(1)
Day 
33 
(-1)
every 2 
weeks 
(2 days)
Once monthly 
(2 days)
24 (4) 
hours 
post-last 
dose
7 (1) 
days 
post-last 
dose
14 (2) 
days 
post-last 
dose
every 3 
months 
(2 
weeks)
Review 
eligibility 
criteria for 
treatment
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Directed 
physical exam
X
X
Body height and 
weight/
growth 
percentiles
X
X
Pregnancy testc
X
X
X
X
X
Clinical status 
assessment
X
X
X
X
Assess ALT, 
AST, and BTd
X
X
X
X
X
Assess serum 
sodiume
X
X
X
X
X
X
X
X
X
X
X


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Table 3.7.2-3 Schedule of Assessments for Each Treatment Cycle
Proceduresa
Pre-
treatment 
Baselineb
Titration Phaseb
Post-titration
Treatment 
Cycle 
Month 2
Treatment Cycle 
Month 3+
(Maintenance)
Follow- up Phase
Days 
-4 to -1
Day 
1
Day 
2 
and 
3
Day 
4
Day 
7, 14 
and 
21
Day 
30 
(1)
Day 
33 
(-1)
every 2 
weeks 
(2 days)
Once monthly 
(2 days)
24 (4) 
hours 
post-last 
dose
7 (1) 
days 
post-last 
dose
14 (2) 
days 
post-last 
dose
every 3 
months 
(2 
weeks)
Tolvaptan 
dosingf
X
X
X
X
X
X
X
X
Confirm stable 
dose
X
Dispense 
tolvaptan drug 
kit
X
X
X
X
Assess need for 
continued 
treatment
X
Tolvaptan 
collection/
reconciliation
X
X
X
X
X
PK sample 
collectiong
X
X
Telephone call
X
X
Concomitant 
medications
Adverse events
aAssessments that are part of a Core Safety Follow-up Component Trial Visit which happens to overlap with a visit in the Optional Tolvaptan Treatment 
Component only need to be performed once.


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bCycles can be repeated per clinical need.  If a subject is off tolvaptan treatment for > 72 hours, titration/reinitiation of tolvaptan will require reassessment of 
eligibility criteria and will begin in a hospital setting.
cSerum or urine pregnancy tests will be performed on female subjects 12 years of age and female subjects < 12 years of age if menstruation has started.  In 
Treatment Cycle Month 2 a pregnancy test should be performed a month after the previous assessment.
dIn Treatment Cycle Month 2 liver function should be assessed a month after the previous assessment.
eSerum sodium will be assessed at the pretreatment baseline 48 hours prior to tolvaptan administration where 2 serum sodium assessments (<130 mEq/L 
[mmol/L) must be collected at least 12 hours apart.  On Day 1 a STAT serum sodium sample will be assessed at 2 to 4 hours prior to first dose and another 
sample at 8 hours post-dose.  On Day 2, 3 and 4 a sample will be assessed at 24 (4) hours post previous dose.  On Days 7, 14, 21, and 30 at 24 (4) hours 
post-previous dose.  At Day 33 serum sodium will be assessed between 48 and 72 hours post previous dose.  In Treatment Cycle Month 2 a sample will be 
assessed every 14 (2) days.  In Treatment Cycle Month 3 a sample will be assessed every month (2 days).


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Section 3.7.3.1 
Core Safety 
Follow-up 
Component
New section in this amendment
No text in this section
Section 3.7.3.1.1 
Baseline for Core 
Safety Follow-up 
Component
Section 3.7.3.1 Baseline
The last visit of the previous trial will serve as the Baseline Visit.  
All assessments can be carried over to this trial.  The following 
procedures will be performed during the Baseline Visit (Day 1) to 
ensure the subject qualifies for the trial:
1)
Trial procedures and information regarding the nature of 
the trial will be reviewed and written informed 
consent/assent will be obtained prior to any trial-related 
procedures.  Informed consent/assent needs to be obtained 
only before entering the trial for the first time.
d)
ICF, assent, and/or PIS will be obtained from each 
subject’s parent or legal guardian prior to any trial 
procedures being conducted.
e)
Each subject will indicate willingness to participate in 
the trial by signing or marking an assent form (as 
applicable) supplied for this purpose.
2)
Inclusion criteria will be reviewed.
3)
Demographic information will be collected only before 
enrolling in the trial; data can be carried over from the 
previous trial.
4)
Medical and hyponatremia history will be recorded 
separately; data can be carried over from the previous trial.  
Medical history should include the subject’s current list of 
medical problems.  The hyponatremia medical history 
should include the etiology of subject’s hyponatremia 
(including tests per protocol) and what treatment was 
administered before trial enrollment.  A detailed history 
specific to etiology of hyponatremia will also be recorded.
5)
Any observable symptoms of hyponatremia will be 
assessed and recorded separately.
6)
Serum chemistry laboratory samples (see Table 3.7.3.2.1-
Section 3.7.3.1.1 Baseline for Core Safety Follow-up Component
For all subjects who enroll in this trial, the final laboratory 
assessments in the previous trial can serve as the baseline laboratory 
assessments.   The following procedures will be performed during 
the baseline visit: 
1)
Trial procedures and information regarding the nature of 
the trial will be reviewed and written informed 
consent/assent will be obtained prior to any trial-related 
procedures.  Informed consent/assent needs to be obtained 
only before entering the trial for the first time.
f)
ICF, assent, and/or PIS will be obtained from each 
subject’s parent or legal guardian prior to any trial 
procedures being conducted.
g)
Each subject will indicate willingness to participate in 
the trial by signing or marking an assent form (as 
applicable) supplied for this purpose.
2)
Inclusion criteria will be reviewed.
3)
Demographic information will be collected. 
4)
Medical and hyponatremia history will be recorded 
separately.  Medical history should include the subject’s 
current list of medical problems in addition to the history 
recorded for the prior trial.  The hyponatremia medical 
history should include the etiology of subject’s 
hyponatremia (including the tests specified in 
Section Error! Reference source not found.) and what 
treatment was administered before trial enrollment.  A 
detailed history specific to etiology of hyponatremia will 
also be recorded.
5)
Any observable symptoms of hyponatremia will be 
assessed and recorded separately.
6)
Vital signs (blood pressure, heart rate, respiratory rate, and 


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1) will be transferred from the last assessments from the 
previous trial or collected, as appropriate.
7)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be transferred from the last assessments 
from the previous trial or assessed after the subject has 
been supine for 3 minutes, as appropriate.  Vital signs 
should be performed prior to the blood draws.
8)
A directed physical examination will be transferred from 
the last assessments from the previous trial or performed, 
as appropriate.
9)
Body height and weight will be transferred from the last 
assessments from the previous trial or measured, as 
appropriate, and body mass index will be calculated.
10) Tanner Staging will be transferred from the last 
assessments from the previous trial or completed as part of 
the physical examination, as appropriate.
11) Quality of Life assessments will be transferred from the 
last assessments from the previous trial or performed as 
part of the physical examination, as appropriate.
12) Concomitant medications will be recorded.
13) Adverse events will be assessed.
temperature) will be transferred from the last assessments 
from the previous trial or assessed after the subject has 
been supine for 3 minutes, as appropriate.  Vital signs 
should be performed prior to the blood draws.
7)
A directed physical examination will be transferred from 
the last assessments from the previous trial or performed, 
as appropriate.
8)
Body height and body weight will be transferred from the 
last assessments from the previous trial or measured, as 
appropriate. 
9)
Growth percentile will be calculated.  Prior growth 
development information should also be collected, if 
available.
10) Tanner Staging will be transferred from the last 
assessments from the previous trial or completed as part of 
the physical examination, as appropriate.  Historical 
staging information should also be collected, if available.
11) The final laboratory assessments from the previous trial 
can serve as baseline laboratory assessments in this trial
(see Appendix 6), as appropriate.
12) Serum sodium will be assessed.
13) Neurocognitive assessments will be performed, as 
appropriate by age and where available, within 1 hour of 
the blood draw for serum sodium assessment.
14) Quality of Life assessment will be performed, as 
appropriate by age and where available.
15) Concomitant medications will be recorded.
16) Adverse events will be assessed.
Section 3.7.3.1.2 
Months 1, 3, and 
5
Section 3.7.1.2 Months 1, 3, and 5
Subjects and/or their parents or legal guardians will be contacted by 
telephone or via a visit at the end of Months 1, 3, and 5 (2 weeks) 
to assess any new or ongoing AEs and to collect information on any 
medications administered since the last visit.
Section 3.7.3.1.2 Months 1, 3, and 5
Subjects and/or their parents or legal guardians will be contacted by 
telephone or will be asked to attend a clinical trial site visit at the 
end of Months 1, 3, and 5 (+ 2 weeks) to assess any new or ongoing 
AEs and to collect information on any medications administered 
since the last visit.
Section 3.7.3.1.3 
Section 3.7.1.3 Months 2, 4, and 6/Early Termination
Section 3.7.3.1.3 Months 2, 4, and 6/Early Termination


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Months 2, 4, and 
6/Early 
Termination
Subjects will return to the clinic at the end of Months 2, 4, and 6 (
2 weeks) or at early termination (ET) and the following assessments 
will be performed:
1)
A blood sample for ALT and AST testing (with reflexive 
total bilirubin assessed if the ALT, AST, or both values are 
> 3 ULN) will be collected at Month 2 or at ET, if ET 
occurs before Month 2.
2)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed at each visit after the subject 
has been supine for 3 minutes.  Vital signs should be 
performed prior to the blood draws.
3)
A directed physical examination will be performed at each 
visit.
4)
Body height and weight will be measured at each visit.
5)
Tanner Staging will be completed at Month 6 or at ET.
6)
Quality of Life assessments will be performed at each visit 
as part of the physical examination.
7)
Concomitant medications will be recorded.
8)
Adverse events will be assessed.
Subjects will return to the clinical trial site at the end of Months 2, 
4, and 6 (+ 2 weeks) or at early termination (ET) and the following 
assessments will be performed:
1)
Medical and hyponatremia history will be recorded 
separately.  Medical history should include the subject’s 
current list of medical problems in addition to the history 
recorded for the prior trial.  The hyponatremia medical 
history should include the etiology of subject’s 
hyponatremia (including the tests specified in Section 
3.2.2) and what treatment was administered before trial 
enrollment.  A detailed history specific to etiology of 
hyponatremia will also be recorded.
2)
Any observable symptoms of hyponatremia will be 
assessed and recorded separately.
3)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed at each visit after the subject 
has been supine for 3 minutes.  Vital signs should be 
performed prior to the blood draws.
4)
A directed physical examination will be performed at each 
visit.
5)
Body height will be measured at each visit.
6)
Body weight will be measured at each visit.
7)
Growth percentile will be calculated.
8)
Tanner Staging will be completed at the Month 6 clinical 
trial site visit or at ET according to the instructions 
specified in Section 3.7.5.6 and Appendix 4. 
9)
A blood sample for serum sodium, ALT, AST, and BT will 
be collected at 24 hours (4 hours) post-last dose. 
10) Neurocognitive assessments will be performed, as 
appropriate by age and where available, within 1 hour of 
the blood draw for serum sodium assessment. 
11) Quality of Life assessment will be performed, as 
appropriate by age and where available.
12) Concomitant medications will be recorded.
13) Adverse events will be assessed.


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Section 3.7.3.2 
Optional 
Tolvaptan
Treatment 
Component
Section 3.7.1.4 Schedule of Assessments for Tolvaptan 
Treatment
All assessments to be conducted while subjects are treated with 
tolvaptan should be synchronized with those collected as part of the 
overall trial as possible (ie, assessments should not be performed 
twice at the same time point).  Cycles can be repeated per clinical 
need during the initial 6 months of the trial and/or after the subject 
has completed the initial 6 months of follow-up.  If a subject is off 
of tolvaptan treatment for 48 hours, reinitiation of treatment will 
require reassessment of the eligibility criteria and should begin in a 
hospital setting.
Section 3.7.3.2 Optional Tolvaptan Treatment Component
The procedures to be performed at the required visits for subjects in 
need of tolvaptan treatment and for each tolvaptan treatment cycle 
are summarized in this section. 
If possible, all assessments while subjects are treated with tolvaptan 
should be synchronized with those performed as part of the core 
safety follow-up component of the trial (ie, assessments should not 
be performed twice at the same time point).  Cycles can be repeated 
per clinical need during the initial 6 months of the trial and/or after 
the subject has completed the initial 6 months of follow-up.  If a 
subject is off tolvaptan treatment for > 72 hours, titration and 
reinitiation of treatment will require reassessment of the eligibility 
criteria and will begin in a hospital setting. 
Section 3.7.3.2.1 
Pretreatment 
Baseline Visit
Section 3.7.1.4.1 Pretreatment Baseline Visit
The following procedures will be performed during the Pretreatment 
Baseline Visit (Days −4 to −1) to ensure the subject qualifies for 
treatment with tolvaptan:
1)
Eligibility criteria for tolvaptan treatment will be reviewed.
2)
Medical and hyponatremia history will be recorded 
separately.  Medical history should include the subject’s 
current list of medical problems that impacts the subject’s 
current hospital stay.  The hyponatremia medical history 
should include the etiology of subject’s hyponatremia 
(including tests per protocol) and what treatment was 
administered before trial enrollment.  A detailed history 
specific to the etiology of hyponatremia will also be 
recorded.
3)
Any observable symptoms of hyponatremia will be 
assessed and recorded separately.
4)
A urine pregnancy test will be performed for female 
subjects 12 years of age and female subjects < 12 years 
of age if menstruation has started.
5)
A blood sample for ALT and AST testing (with reflexive 
Section 3.7.3.2.1 Pretreatment Baseline Visit
For subjects with a clinical need for tolvaptan treatment, the 
baseline visit for the core safety follow-up component of the trial 
may serve as the pretreatment baseline visit for the optional 
tolvaptan treatment component.  The following procedures will be 
performed during the pretreatment baseline visit (Days −4 to −1) to 
ensure the subject qualifies for each tolvaptan treatment cycle:
1)
Eligibility criteria (see Appendix 5) will be reviewed.
2)
A clinical status assessment will be performed. 
3)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed at each visit after the subject 
has been supine for 3 minutes.  Vital signs should be 
performed prior to the blood draws.
4)
A directed physical examination will be performed.
5)
Body height will be measured.
6)
Body weight will be measured.
7)
Growth percentile will be calculated.
8)
A blood sample for ALT, AST, and BT will be collected.
9)
A serum or urine pregnancy test will be performed on 
female subjects 12 years of age and female subjects 


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total bilirubin assessed if the ALT, AST, or both values are 
> 3 ULN) will be collected.
6)
Within 48 hours prior to tolvaptan administration, 
2 samples for serum sodium testing will be collected at 
least 12 hours apart.  These sample collections may be 
waived if they occur within 48 hours of the last dose of 
tolvaptan or as past standard of care within 48 hours prior 
to tolvaptan administration.
7)
A directed physical examination will be performed.
8)
Concomitant medications will be recorded.
9)
Adverse events will be assessed.
< 12 years of age if menstruation has started.
10) Within 48 hours prior to tolvaptan administration, 
2 samples for serum sodium testing will be collected at 
least 12 hours apart.
11) Concomitant medications will be recorded.
12) Adverse events will be assessed.
Section 3.7.3.2.2 
Titration Phase
Section 3.7.1.4.2 Titration Period
Section 3.7.3.2.2 Titration Phase
Section 
3.7.3.2.2.1 Day 1
Section 3.7.1.4.2.1 Day 1
Subjects will be administered the first dose of tolvaptan (initially 
and for reinitiation of treatment) in a hospital setting.  The following 
procedures will be performed on Day 1:
1)
Blood samples for serum sodium testing should be 
collected STAT at baseline (within 3 [1] hours prior to 
dosing) and minimally 8 hours post-first dose per protocol; 
serum sodium may be further assessed as per clinician 
preference during the first 24 hours post-first dose.
2)
Any observable symptoms of hyponatremia will be 
assessed at baseline (prior to dosing) to confirm eligibility.
3)
Tolvaptan will be administered as a 3.75-, 7.5-, or 15-mg 
dose based on age, weight, and the use of CYP3A4 
inhibitors.
4)
Concomitant medications will be recorded.
5)
Adverse events will be assessed.
Section 3.7.3.2.2.1 Day 1
Subjects will be administered the first dose of tolvaptan (initially 
and for reinitiation of treatment, if the latter occurs > 72 hours after 
a discontinuation) in a hospital setting.  The following procedures 
will be performed on Day 1:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been 
supine for 3 minutes.  Vital signs should be assessed 
prior to blood draws.
2)
A blood sample for STAT serum sodium testing will be 
collected within 2 to 4hours prior to dosing.  Results need 
to be reviewed prior to dosing to confirm continued 
treatment eligibility of the subject.
3)
Tolvaptan will be administered.
4)
A blood sample for serum sodium testing will be collected 
8 hours post-first dose in the current treatment cycle.
5)
Concomitant medications will be recorded.
6)
Adverse events will be assessed.
Section 
3.7.3.2.2.2 Day 2 
up to Day 4
Section 3.7.1.4.2.2 Day 2 Through the End of the Titration 
Period
Section 3.7.3.2.2.2 Day 2 up to Day 4
...


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...
1)
A blood sample for serum sodium testing must be assessed 
at 24 (4) hours post-previous dose with the results 
reviewed prior to subsequent tolvaptan dosing.
2)
Tolvaptan will be titrated per the titration guidelines 
(Section 3.2.1 for the assigned weight group.
3)
At the end of the titration period, sufficient IMP will be 
dispensed for subjects that are outpatients for once daily 
dosing until their next scheduled visit.  Subjects and their 
parents/legal guardians will be instructed to return any 
remaining IMP at the next visit for dose reconciliation.
...
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been 
supine for 3 minutes.  Vital signs should be assessed 
prior to blood draws.
2)
A blood sample for serum sodium testing must be assessed 
at 24 (4) hours post-previous dose with the results 
reviewed prior to subsequent tolvaptan dosing.
3)
Administer tolvaptan.  Tolvaptan will be titrated per the 
titration guidelines (see Section 3.2.1.2) for the assigned 
weight group.
4)
On Day 4, if a stable dose of tolvaptan has been confirmed, 
the initial titration phase will conclude, and sufficient 
tolvaptan will be dispensed for subjects that are outpatients 
for QD dosing until their next scheduled visit.  Subjects 
and their parents/legal guardians will be instructed to return 
any remaining tolvaptan at the next visit for dose 
reconciliation.
...
Section 3.7.3.2.3
Days 7, 14, and 
21
New section in this amendment
Serum sodium will be assessed a minimum of once weekly during 
the first month of the treatment cycle, on the morning of Days 7, 14, 
and 21before the next dose of tolvaptan.
The following assessments will be performed during each in-clinic 
visit during the first month of the treatment cycle:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been 
supine for 3 minutes.  Vital signs should be assessed 
prior to blood draws.
2)
A blood sample for serum sodium testing must be assessed 
at 24 (4) hours post-previous dose with the results 
reviewed prior to subsequent tolvaptan dosing.
3)
Tolvaptan will be administered.
4)
Concomitant medications will be recorded.
5)
Adverse events will be assessed.


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Section 3.7.3.2.4 
30 (1) Days 
Post-first Dose
New section in this amendment
After 30 days of tolvaptan treatment, all subjects should discontinue 
treatment for assessment of continued need for tolvaptan treatment.  
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been 
supine for 3 minutes.  Vital signs should be assessed 
prior to blood draws.
2)
A blood sample for serum sodium testing must be assessed 
at 24 (4) hours post-previous dose with the results 
reviewed prior to subsequent tolvaptan dosing.
3)
A blood sample for ALT, AST, and BT will be collected.
4)
Tolvaptan will be administered.
5)
Advise subject to skip the next 2 doses.
6)
Concomitant medications will be recorded.
7)
Adverse events will be assessed.
Section 3.7.3.2.5 
Day 33 (- 1)
New section in this amendment
The following assessments will be performed:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been 
supine for 3 minutes.  Vital signs should be assessed 
prior to blood draws.
1)
A clinical status assessment will be performed.
2)
A serum or urine pregnancy test will be performed at each 
visit on female subjects 12 years of age and female 
subjects < 12 years of age if menstruation has started.
3)
A blood sample for serum sodium testing must be assessed 
to confirm the need for continuation of treatment.  Refer to
Figure 3.1-1 and Section 3.2.2 for the trial schematic and a 
description of the treatment continuation decision.
4)
Tolvaptan will be administered if need for continued 
treatment is confirmed. 
Subjects who reinitiate treatment at the same dose or a 
lower dose of tolvaptan after discontinuation for up to 
72 hours will not be required to reinitiate treatment in a 


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hospital setting.  If subjects are off tolvaptan treatment for 
> 72 hours, reinitiation of treatment, starting with titration 
(Section 3.2.1.2), will require reassessment of the 
eligibility criteria, and titration will begin in a hospital 
setting.  Tolvaptan should be titrated with regular serum 
sodium assessments.
5)
Concomitant medications will be recorded.
6)
Adverse events will be assessed.
Section 3.7.3.2.6 
Treatment Cycle 
Month 2: Every 2 
Weeks (2 days)
New section in this amendment
The next clinic visit should occur 2 weeks after the decision to 
continue treatment is made and then 2 weeks thereafter if treatment 
is continued.
The following assessments will be performed during each in-clinic 
visit during the second month of each treatment cycle:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been 
supine for 3 minutes.  Vital signs should be assessed 
prior to blood draws.
2)
A blood sample for serum sodium testing must be assessed 
at 24 (4) hours post-previous dose with the results 
reviewed prior to subsequent tolvaptan dosing.
3)
A blood sample for ALT, AST, and BT will be collected 
(at the end of Treatment Cycle Month 2).
4)
For each treatment cycle, a single PK blood sample will be 
collected after 8 consecutive weeks of tolvaptan dosing for 
the determination of tolvaptan and metabolites plasma 
concentrations.
5)
A clinical status assessment will be performed.
6)
A serum or urine pregnancy test will be performed at each 
visit on female subjects 12 years of age and female 
subjects < 12 years of age if menstruation has started (at 
the end of Treatment Cycle Month 2 only).
7)
Tolvaptan will be administered.
8)
Sufficient tolvaptan will be dispensed for subjects that are 


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outpatients for QD dosing until their next scheduled visit.  
Subjects and their parents/legal guardians will be instructed 
to return any remaining tolvaptan at the next visit for dose 
reconciliation.
9)
Concomitant medications will be recorded.
10) Adverse events will be assessed.
Section 3.7.3.2.7 
Maintenance 
Phase
New Section in this amendment
No Text in this section
Section 
3.7.3.2.7.1 
Treatment Cycle 
Month 3 (and 
every month 
thereafter) 
(2 days)
Section 3.7.1.4.3 Maintenance Period
Subjects will return to the site for safety and assessment of serum 
sodium concentrations at intervals discussed in Section 3.1.1.1.  The 
following procedures will be performed:
1)
A urine pregnancy test will be performed at each visit on 
female subjects 12 years of age and female subjects < 12 
years of age if menstruation has started.
2)
A blood sample for ALT and AST testing (with reflexive 
total bilirubin assessed if the ALT, AST, or both values are 
> 3 ULN) will be collected every month (2 days).
3)
A blood sample for serum sodium testing should be taken 
at each visit.
4)
Tanner Staging will be completed every 6 months.
5)
Tolvaptan will be administered once daily.
6)
Sufficient IMP will be dispensed for subjects that are 
outpatients for once daily dosing until their next scheduled 
visit.  Subjects and their parents/legal guardians will be 
instructed to return any remaining IMP at the next visit for 
dose reconciliation.
7)
For each initiation or reinitiation of tolvaptan treatment, a 
single blood sample will be collected after 8 consecutive 
weeks of tolvaptan dosing for the determination of 
tolvaptan and metabolites plasma concentrations.
8)
Concomitant medications will be recorded.
9)
Adverse events will be assessed.
Section 3.7.3.2.7.1 Treatment Cycle Month 3 (and every month 
thereafter) (2 days)
Subjects will return to the clinical trial site for assessment of safety 
and of serum sodium concentrations at the intervals discussed in 
Section 3.1.2.  The following procedures will be performed:
1)
A serum or urine pregnancy test will be performed at each 
visit on female subjects 12 years of age and female 
subjects < 12 years of age if menstruation has started.
2)
A directed physical examination will be performed.
3)
A clinical status assessment will be performed.
4)
A blood sample for ALT, AST, and BT will be collected 
every month.
5)
A blood sample for serum sodium testing should be taken 
at each visit.
6)
Tolvaptan will be administered.
7)
Sufficient tolvaptan will be dispensed for subjects that are 
outpatients for QD dosing until their next scheduled visit.  
Subjects and their parents/legal guardians will be instructed 
to return any remaining tolvaptan at the next visit for dose 
reconciliation.
8)
If a PK sample has not been taken at the end of the 
Treatment Cycle Month 2 visits, a single PK blood sample 
will be collected after 8 consecutive weeks of tolvaptan 
dosing for the determination of tolvaptan and metabolites 
plasma concentrations.
9)
Concomitant medications will be recorded.


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10) Adverse events will be assessed.
Tolvaptan treatment cycles may be repeated per a subject’s clinical 
need and the discretion of the investigator. Subjects may be 
evaluated for continued need for tolvaptan treatment at additional 
clinical trial site visits per the investigator’s discretion.  After 
discontinuation of tolvaptan, serum sodium concentrations will be 
assessed at 24 (4) hours and at 7 (+ 1) days post-last dose. 
Section 3.7.3.2.8 
Follow-up Phase
New section in this amendment
No text in this section.
Section 
3.7.3.2.8.1 First 
Follow-up: 24 
(4) hours post-
last dose
Section 3.7.1.4.4 Initial Follow-up Visit
After discontinuation from treatment, the subject must return to the 
site at approximately 48 (4) hours post-last dose.  The following 
procedures will be performed:
1)
A urine pregnancy test will be performed on female 
subjects 12 years of age and female subjects < 12 years 
of age if menstruation has started.
2)
A blood sample for serum sodium testing should be 
obtained at 48 (4) hours post-last dose.
3)
Any remaining IMP will be collected from the subjects.
4)
Concomitant medications will be recorded.
5)
Adverse events will be assessed.
Section 3.7.3.2.8.1 First Follow-up: 24 (4) hours post-last dose
After discontinuation from treatment, the subject must return to the 
site at approximately 24 (4) hours post-last dose.  The following 
procedures will be performed:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been 
supine for 3 minutes.  Vital signs should be assessed 
prior to blood draws.
2)
A blood sample for ALT, AST, and BT testing will be 
collected.
3)
A serum or urine pregnancy test will be performed on 
female subjects 12 years of age and female subjects 
< 12 years of age if menstruation has started (if not done 
within the last 30 days).
4)
A blood sample for serum sodium testing will be collected 
at 24 (4) hours post-last dose.
5)
Any remaining tolvaptan will be collected from the 
subjects.
6)
Concomitant medications will be recorded.
7)
Adverse events will be assessed.
Section 
3.7.3.2.8.2
Second Follow-
Section 3.7.1.4.5 7-day Follow-up Visit
A follow-up visit will occur 7 (+ 1) days after the last dose of trial 
Section 3.7.3.2.8.2 Second Follow-up: 7 (1) days post-last dose
An additional follow-up visit will occur 7 (1) days post-last dose. 


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up: 7 (1) days 
post-last dose
medication.
1)
A blood sample for serum sodium testing will be collected.
2)
A blood sample for ALT and AST testing (with reflexive 
total bilirubin assessed if the ALT, AST, or both values are 
> 3 ULN) will be collected.
3)
Concomitant medications will be recorded.
4)
Adverse events will be assessed.
Cycles may be repeated per a subject’s clinical need and the 
discretion of the investigator.
The following assessments will be performed:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been 
supine for 3 minutes.  Vital signs should be assessed 
prior to blood draws.
2)
A blood sample for serum sodium testing will be collected.
3)
Concomitant medications will be recorded.
4)
Adverse events will be assessed.
Section 
3.7.3.2.8.3 Third 
Follow-up: 14 
(2) days post-
last dose
New section in this amendment
A follow-up telephone contact will occur at 14 (2) days post-last 
dose for assessment of adverse events and concomitant medications.
3)
Concomitant medications will be recorded.
4)
Adverse events will be assessed.
Section 
3.7.3.2.8.4 
Additional 
Follow-up 
Contacts
New section in this amendment
Follow-up telephone contacts will occur every 3 months (2 weeks) 
for all subjects who are not receiving tolvaptan treatment.
1)
Concomitant medications will be recorded.
2)
Adverse events will be assessed.
Section 3.7.4 
Efficacy 
Assessments
Section 3.7.2 Efficacy Assessments
See Section 3.7.5.
Section 3.7.4 Efficacy Assessments
No text in this section
Section 3.7.4.1 
Serum Sodium
Concentrations
New section in this amendment
No text in this section
Section 3.7.4.1.1 
Pretreatment
Baseline Visit
New section in this amendment
All subjects should have blood samples collected for serum sodium 
assessment at the baseline visit or transferred from the last visit of 
the previous trial.  Within 48 hours prior to tolvaptan 
administration, 2 blood samples will be collected at least 12 hours 
apart for assessment of baseline serum sodium to determine subject 
eligibility for tolvaptan treatment.  A third serum sodium sample 
should be drawn within 2 to 4 hours prior to dosing; the results must 
be verified to be < 130 mEq/L (mmol/L) prior to the first dose in 
each treatment cycle.


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Section 3.7.4.1.2 
Initial Titration 
Phase and 
Month 1
New section in this amendment
During the Titration Phase (the first 30 days of treatment) subjects 
should have serum sodium assessments at a minimum of QD on 
Day 1 up to  Day 4 of treatment, and at a minimum of once weekly 
thereafter (ie, on Days 7, 14, 21, and 28 of Month 1).  On Day 1, a 
serum sodium sample should be collected STAT and recorded in the 
CRF at a minimum of 8 hours post-first dose and 24 (4) hours 
post-previous dose. 
Section 3.7.4.1.3 
Assessment of 
Continued Need 
for Tolvaptan 
Treatment
New section in this amendment
Tolvaptan administration will be discontinued after 30 days of 
treatment to assess the subjects’ need for continued treatment.  
Procedures for reinitiation of tolvaptan treatment for subjects with a 
clinical need per the investigator’s assessment are described in 
Section Error! Reference source not found..  During the second 
consecutive month of treatment, serum sodium concentrations 
should be assessed at a minimum of every 2 weeks (2 days).
Section 3.7.4.1.4 
Maintenance 
Phase
New section in this amendment
Once subjects have been treated for 2 months, and are on a stable 
dose with no additional titration required, they can be considered to 
enter a Maintenance Phase from the third month onward.  At this 
point, the subjects should return to the clinical trial site at a 
minimum of once per month (2 days) for assessment of serum 
sodium concentrations.  When a subject is discontinued from 
tolvaptan, serum sodium must be assessed at 24 (4) hours, and at 
7 (1) days post-last dose.
Section 3.7.4.1.5 
Unscheduled 
Assessments
New section in this amendment
Additional unscheduled serum sodium assessments may be 
performed at the discretion of the clinical investigator and other 
physicians of record, depending on the local standards and subject’s 
clinical condition.  All serum sodium concentrations collected as 
part of standard of care will be reported as unscheduled sodium 
assessments in the electronic CRF through the follow-up sodium 
assessments.
Section 3.7.4.2 
Quality of Life 
Assessments
New section in this amendment
Two patient-reported outcomes instruments (acute versions with 
7 day recall period) will be used to assess subject quality of life: 
PedsQL Generic Core Scale and PedsQL Multidimensional Fatigue 
Scale.  Both instruments are appropriate for 2 years of age, 
however availability may be limited for certain ages and languages.  
The age groups covered by these assessments are Toddler 


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(2-4 years), Young child (5–7 years), Child (8–12 years), and 
Adolescent (13–18 years). Depending on the subject’s age, the 
questionnaire may be completed by either the subject or the 
parent/caregiver, as appropriate.
The PedsQL Generic Core Scale consists of 23 items encompassing 
physical, emotional, social, and school domains.  
The PedsQL Multidimentional Fatigue Scale consists of 18 items in 
3 subscales: general fatigue, sleep/rest fatigue, and cognitive 
fatigue. The instrument focuses on the domains of processing 
speed, attention/vigilance, visual and working memory.  
The assessment time points are at Baseline, Month 2, Month 4, and 
at Month 6 or Early Termination during the Core Safety Follow-up 
Component.
Section 3.7.5 
Safety 
Assessments
Section 3.7.3 Safety Assessments 
No text in this section
Section 3.7.5 Safety Assessments
Safety will be assessed through the monitoring of AEs, clinical 
laboratory tests, vital signs, body weight, directed physical 
examinations, neurological examinations, rescue therapy, and fluid 
restriction.  Body height, body weight, Tanner Staging and baseline 
laboratory assessments can be carried over from the previous trial of 
titrated oral IMP to this trial, if no more than one month passes 
between trials.
The monitoring frequency of safety assessments is at the discretion 
of the clinical investigator; however, the trial requires the minimum 
sample collection for all subjects noted in Section 3.7.5.2.
Section 3.7.5.1 
Adverse Events
Section 3.7.3.1 Adverse Events
Refer to Section 5, Reporting of Adverse Events.
In particular, the following AEs must be actively monitored:  
absolute serum sodium level 145 mmol/L, overly rapid rise in 
serum sodium defined as an increase in serum sodium of > 8 
mmol/L over a 10-hour period, 12 mmol/L over a 24-hour period, 
or a rate of increase in serum sodium that the investigator deems too 
rapid, neurological symptoms, or other signs or symptoms 
suggestive of osmotic demyelination (see Section 5.3.1 for more 
Section 3.7.5.1 Adverse Events
Refer to Section 5, Reporting of Adverse Events.
In addition, for subjects on tolvaptan treatment active monitoring is 
required for:

Absolute serum sodium level 145 mEq/L (mmol/L) or an 
overly rapid correction of the serum sodium level (an 
increase in serum sodium of > 8 mEq/L [mEq/L (mmol/L)] 
over a 10-hour period, 12 mEq/L [mEq/L (mmol/L)] over 
a 24-hour period, or a rate of correction in serum sodium 


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detail).
concentration that the investigator deems too rapid), 
neurologic symptoms, or other signs or symptoms 
suggestive of osmotic demyelination (see Section 5.3.1for 
more details).

Elevations in AST or ALT that are 2 ULN or levels 
that increase 2 times their previously observed level.  If 
this occurs, a BT level should also be evaluated.  See
Section 3.7.3.5.1 for more information and Section 5.4 for 
detailed instructions on how this type of event should be 
captured.

Worsening symptoms of hyponatremia

Hypovolemia or hypotension requiring intervention.
Section 3.7.5.2 
Clinical 
Laboratory Tests: 
Core Safety 
Follow-up 
Component
Section 3.7.3.2 Clinical Laboratory Tests
Table 3.7.3.2-1 presents the protocol-required clinical laboratory 
results (serum chemistry, including liver function tests) that are 
reported as part of the trial results.  Serum chemistry will either be 
measured at Baseline or transferred from the last visit of the 
previous trial.  At Month 2 or at ET, if ET occurs before the Month 
2 Visit, only ALT and AST (with reflexive total bilirubin 
assessment if the ALT, AST, or both values are > 3 ULN) will be 
measured.  No further laboratory assessments are required per 
protocol except as needed for the follow-up of AEs.
Table 3.7.3.2-1
Safety Clinical Laboratory 
Tests for All Subjects
Section 3.7.5.2 Clinical Laboratory Tests:  Core Safety Follow-
up Component 
For all subjects enrolled in the core safety follow-up component, 
serum sodium assessments and LFTs will either be performed at 
baseline or transferred from the last visit of the previous trial.  At 
Months 2, 4, and 6, serum sodium will be assessed.  At Month 2 or 
at ET, if ET occurs before the Month 2 Visit, ALT, AST, and BT 
will be measured.  No further laboratory assessments are required 
per protocol except as needed for the follow-up of AEs.


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Serum Chemistry:
ALT
Alkaline phosphatase
AST
Bicarbonate (or carbon 
dioxide)
Bilirubin, total
Blood urea nitrogen
Calcium
Chloride
Cholesterol, total
Creatinine
Gamma glutamyl transferase
Glucose
Lactic dehydrogenase
Potassium
Protein, total
Sodium
Triglycerides
Uric acid
Section 3.7.5.3 
Clinical 
Laboratory Tests: 
Optional 
Tolvaptan 
Treatment 
Component
Section 3.7.3.2.1 Clinical Laboratory Tests for Tolvaptan 
Treatment
Table 3.7.3.2.1-1 presents the protocol-required clinical laboratory 
results (serum sodium, ALT, and AST with reflexive total bilirubin 
assessment if the ALT, AST, or both values are > 3 ULN) that are 
reported as part of the trial results for subjects on tolvaptan.  If these 
results are to be obtained as part of the standard of care for the 
subject, the timing should be coordinated per the schedule of 
assessments (Table 3.7-2), whenever possible, to minimize the 
number of blood draws for the subject.
Section 3.7.5.3 Clinical Laboratory Tests: Optional Tolvaptan 
Treatment Component
Table 3.7.5.3-1 presents the protocol-required clinical laboratory 
results (serum sodium, ALT, AST, and BT) that are reported as part 
of the trial results for subjects in the optional tolvaptan treatment 
component.  If these results are to be obtained as part of the standard 
of care for the subject, the timing should be coordinated per the 
schedule of assessments (Section 3.7.3), whenever possible, to 
minimize the number of blood draws for the subject while at the 
same time ensuring that liver function tests are monitored on a 
monthly basis while continuing treatment with tolvaptan.
Table 3.7.5.3-1
Safety Clinical 
Laboratory Tests 
During 
Tolvaptan 
Treatments
Table 3.7.3.2.1-1
Safety Clinical Laboratory 
Tests During Tolvaptan 
Treatment
Table 3.7.5.3-1
Safety Clinical Laboratory 
Tests During Tolvaptan 
Treatment


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ALT
AST
Reflexive total bilirubin
Efficacy:
Serum sodium
Additional Tests:
Urine pregnancy test (if 
applicable)
ALT
AST
BT
Efficacy:
Serum sodium
Additional Tests:
Serum or urine pregnancy 
test (if applicable)
Section 3.7.5.3.1 
Monitoring of 
Liver 
Transaminases
Section 3.7.3.2.2 Monitoring of Liver Transaminases
Long term use of tolvaptan has demonstrated the potential to cause a 
clinically significant elevation in laboratory tests of liver function.  
Based on previous research in the adult polycystic kidney disease 
population, the expected onset of the elevation is between 3 and 14 
months of chronic treatment with tolvaptan.
For a subject that experiences an elevation in AST or ALT that is 
3 ULN or whose levels increase 3 times their previous observed 
value, a total bilirubin level should also be evaluated.  If the total 
bilirubin is 2 ULN or 2 times their previous observed value, 
an immediately reportable event (IRE) form with all values listed 
should be completed and also reported as an AE on the case report 
forms (CRFs).  See Section 5.4 for detailed instructions on how to 
capture this type of event.
Section 3.7.5.3.1 Monitoring of Liver Transaminases
Long-term use of tolvaptan has demonstrated the potential to cause 
a clinically significant elevation in liver function test values.  Based 
on previous research in the adult polycystic kidney disease 
population, the expected onset of the elevation, if it occurs, is 
between 3 and 14 months of chronic treatment with tolvaptan.
For a subject who experiences an elevation in AST or ALT that is 
2 ULN or whose levels increase 2 times their previous observed 
value, a BT level should also be evaluated.  These elevated values 
should be confirmed by retesting.  If BT is 2 ULN or 2 times 
their previous observed value, an immediately reportable event 
(IRE) form with all values listed should be completed and also 
reported as an AE on the CRFs.  See Section 5.4.1 for detailed 
instructions on how this type of event should be captured.
Section 3.7.5.4 
Physical 
Examination and 
Vital Sign 
Assessments
Section 3.7.3.3 Physical Examination and Vital Sign 
Assessments
...
Body weight will be measured at the Month 2, 4, and 6 Visits.  
Every effort should be made to ensure that body weight 
measurements will be performed in a reproducible and consistent 
manner.  Body weight measurements should be performed at the 
clinical site always using the same scale.  Subjects should wear the 
same type of clothes at each measurement, preferably a gown and 
no shoes.  All body weight measurements should be taken post void.
...
Section 3.7.5.4 Physical Examination and Vital Sign 
Assessments
...
Body weight will be measured at the Month 2, 4, and 6 Visits.  
Every effort should be made to ensure that body weight 
measurements will be performed in a reproducible and consistent 
manner.  Body weight measurements should be performed at the 
clinical trial site always using the same scale.  Subjects should wear 
the same type of clothes at each measurement, preferably a gown 
and no shoes.  All body weight measurements should be taken post 
void.
...


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Section 3.7.5.5 
Tanner Staging
Section 3.7.3.4 Tanner Staging
The collection of Tanner Staging data is required at the Month 6 
Visit or at ET and every 6 months during tolvaptan treatment; every 
attempt should be made to collect this information.  Tanner Staging 
must be completed together with the physical examination by the 
same trial affiliated clinician in the most inconspicuous manner for 
the subject as possible.  Tanner Staging could be completed by the 
trial affiliated pediatrician or family practitioner (additionally 
physician’s assistant or nurse practitioner in the US).  A subject who 
reaches Stage 5 (both in pubic hair and genitalia) does not need to 
continue with Tanner Staging.  Sites should make attempts to have 
examiners of both gender types.  Attempts should be made to have 
the examination performed by the same gender as the subject.  
Otherwise, trial-affiliated personnel of the same gender as the 
subject (ie, nurse) should be in the same examination room as the 
subject.
...
Section 3.7.5.5 Tanner Staging
The collection of Tanner Staging data is required for all subjects in 
the core safety follow-up component at the Month 6 Visit.  Every 
attempt should be made to collect this information.
Tanner Staging must be completed together with the physical 
examination by the same trial affiliated clinician in the most 
inconspicuous manner for the subject as possible.  Tanner Staging 
could be completed by the trial affiliated pediatrician or family 
practitioner (additionally physician’s assistant or nurse practitioner 
in the US).  A subject who reaches Stage 5 (both in pubic hair and 
genitalia) does not need to continue with Tanner Staging.  Sites 
should make attempts to have examiners of both sexes.  Attempts 
should be made to have the examination performed by the same sex 
as the subject.  Otherwise, trial-affiliated personnel of the same sex 
as the subject (ie, nurse) should be in the same examination room as 
the subject.
...
Section 3.7.3.5 
Electrocardiogra
m Assessments
Electrocardiograms (ECGs) will be recorded only as warranted; 
there are no trial mandated ECGs.
This section was removed in this amendment
Section 3.7.5.6 
Hyponaterima 
History
Section 3.7.3.6 Hyponaterima History
Each subject’s hyponatremia medical history will be recorded at 
Baseline.  The hyponatremia history should include the etiology of 
subject’s hyponatremia (including tests per protocol) and what 
treatment was administered before trial enrollment.  Symptoms 
potentially attributable to hyponatremia should be specifically 
assessed for prior history.  The hyponatremia assessment at Baseline 
will consist of documentation of hyponatremia etiology (eg, 
SIADH, hepatocellular disease [including cirrhosis], CHF, or other) 
prior fluid intake and output, and prior hyponatremia treatment, ie, 
fluid restriction, if applicable.  A detailed history specific to etiology 
of hyponatremia will also be recorded.
Section 3.7.5.6 Hyponaterima History
Each subject’s hyponatremia medical history will be recorded at 
baseline.  The hyponatremia history should include the etiology of 
subject’s hyponatremia (including tests per protocol) and what 
treatment was administered before trial enrollment.  Symptoms 
potentially attributable to hyponatremia should be specifically 
assessed for prior history.  The hyponatremia assessment at baseline 
will consist of documentation of hyponatremia etiology (eg, 
SIADH, hepatocellular disease [including cirrhosis], heart failure, or 
other) prior fluid intake and output, and prior hyponatremia 
treatment, ie, fluid restriction, if applicable.  A detailed history 
specific to etiology of hyponatremia will also be recorded.


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Section 3.7.5.7 
Clinical Status 
Assessment
New section in this amendment
Clinical status assessments will be performed per inpatient standard 
of care and should include review of patient chart entries, including 
hyponatremia assessment notes, trial- and nontrial-specific 
laboratory results, any examination findings, medical problem list 
changes, and fluid intake and output to evaluate overall subject 
eligibility in terms of hyponatremia state. The clinical assessment 
will focus on symptoms and signs which will inform treatment 
decisions (eg, the need to switch to rescue therapy, or the ability to 
safely discharge a subject from the hospital). The clinical 
assessment should be performed by a trial investigator who will be 
aware of laboratory and other clinical response data.
Section 3.7.6 
Pharmacokinetic 
Assessments
Section 3.7.4 Pharmacokinetic Assessments
Section 3.7.6 Pharmacokinetic Assessments
Section 3.7.6.1 
Blood Collection 
Times
Section 3.7.4.1 Blood Collection Times
For those subjects undergoing treatment with tolvaptan for at least 
8 consecutive weeks for each initiation or reinitiation of therapy, a 
single blood sample to measure tolvaptan and metabolite 
concentrations at steady state will be obtained for each cycle.  The 
date and time of the PK sample and the date and time of the dose 
given immediately prior to the PK sample will be recorded on the 
CRFs.
Section 3.7.6.1 Blood Collection Times
For subjects undergoing treatment with tolvaptan for at least 
8 consecutive weeks for each initiation or reinitiation of therapy, a 
single blood sample to measure tolvaptan and metabolite 
concentrations at steady state will be obtained for each cycle.  The 
date and time of the PK sample and the date and time of the dose 
given immediately prior to the PK sample will be recorded on the 
CRFs.
For each subject all samples will be collected according to local 
guidelines and best practices for pediatric care.  If a sample is 
missing because of limitations in allowable blood volumes based on 
local regulations or local practice this will not count as a protocol 
deviation.
Section 3.7.7 
Exploratory 
Assessments
Section 3.7.5 Exploratory Assessments
Exploratory assessments include overall serum sodium 
concentrations and daily clinical status assessments.
Section 3.7.7 Exploratory Assessments
Exploratory assessments include a neurocognition test battery. 
These assessments will be performed for all subjects in the core 
safety follow-up component of the trial.
Section 3.7.7.1 
Neurocognitive 
Section 3.7.5.1 Serum Sodium Concentrations
Section 3.7.7.1 Neurocognitive Assessments


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Assessments
Monitoring frequency of serum sodium is at the discretion of the 
clinical investigator; however, it is required to be performed 
minimally once per day during titration.  Please see the minimum 
required sample collection guidelines for all subjects noted in 
Section 3.1.1.1 and Section 3.7.2.
All subjects should have blood samples collected for serum sodium 
assessment at the Baseline Visit or transferred from the last visit of 
the previous trial.  Within 48 hours prior to tolvaptan 
administration, 2 blood samples will be collected at least 12 hours 
apart for assessment of baseline serum sodium to determine subject 
eligibility for tolvaptan treatment.  These sample collections may be 
waived if they occur within 48 hours of the last dose of tolvaptan or 
as past standard of care within 48 hours prior to tolvaptan 
administration.  A third serum sodium sample should be drawn 
within 3 [1] hours prior to dosing; the results must be verified to 
be < 130 mmol/L prior to the first dose.  A serum sodium sample 
should be collected STAT and recorded in the CRF minimally at 
8 hours post-first dose and 24 (4) hours post-previous dose during 
the Titration Period and then minimally during the Maintenance 
Period every 2 weeks (2 days) during Months 1 to 3.  From Month 
4 onward for consecutive treatment, serum sodium should be 
assessed minimally once per month (2 days).  When a subject is 
discontinued from tolvaptan, serum sodium must be assessed at 
48 (4) hours and 7 (+ 1) days post-last dose.
Additional unscheduled serum sodium assessments may be 
performed at the discretion of the clinical investigator and other 
physicians of record, depending on the local standards and subject’s 
clinical condition.  All serum sodium concentrations collected as 
part of standard of care will be reported as unscheduled sodium 
assessments in the electronic CRF through the follow-up sodium 
assessments.
Neurocognitive assessments will be performed at baseline and at 
Months 2, 4, and 6 during the Core Safety Follow-up Component.  
Age appropriate (4-18 years of age) neurocognitive assessments will 
be performed using a computerized test battery provided by 
CogState Ltd.  
The instruments used for this assessment include 4 tests: the 
Detection Test, Identification Test, One Card Learning Test, and 
One Back Test. The tests will focus on the domains of processing 
speed, attention/vigilance, visual memory and working memory.
For subjects 6 to 18 years of age all tests will be administered. For
subjects 4 to 5 years of age, the Detection Test and the Identification 
Test will be administered. Availability of the assessment may be 
limited for certain subject ages and languages.
The assessment time points correlate with serum sodium 
assessments and should occur within an hour of serum sodium 
blood draws.
3.7.8 End of 
Trial
3.7.6 End of Trial
3.7.8 End of Trial


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The End of Trial Date is defined as the last Date of Contact or the 
Date of Final Contact Attempt from the Post-treatment Follow-up 
CRF page for the last subject completing or withdrawing from the 
trial.
The End of Trial Date is defined as the last Date of Contact or the 
Date of Final Contact Attempt from the Follow-up CRF page for the 
last subject completing or withdrawing from the trial.
Section 3.8.1 
Entire Trial or 
Treatment 
Component(s)
Section 3.8.1 Entire Trial or Treatment Arm(s)
Section 3.8.1 Entire Trial or Treatment Component(s)
Section 3.8.3 
Indivdual Subject
...
In addition, subjects meeting the following criteria should have 
results confirmed with a repeat test.  If the result is confirmed, the 
medical monitor should be contacted to consider options of down-
titration, dose interruption, concomitant medication adjustment, 
fluid supplementation, and/or withdrawal:

The subject’s serum sodium increases by > 8 mmol/L in 
any 10-hour period following dosing on Day 1 of a cycle

The subject’s serum sodium increases by 12 mmol/L in 
the 24-hour period following dosing

At any time after dosing, the subject’s serum sodium is 
145 mmol/L.
...
...
In addition, subjects on tolvaptan treatment who meet the following 
criteria should have results confirmed with a repeat test. 

The subject’s serum sodium increases by > 8 mEq/L 
(mmol/L) in any 10-hour period following dosing on Day 1 
of a cycle

The subject’s serum sodium increases by 12 mEq/L 
(mmol/L) in the 24-hour period following dosing

At any time after dosing, the subject’s serum sodium is 
145 mEq/L (mmol/L).

Evidence of dehydration

Abnormal liver function tests (see Section 5.4)
If the result is confirmed, the medical monitor should be contacted 
to consider options of down-titration, dose discontinuation, 
concomitant medication adjustment, fluid supplementation, and/or 
withdrawal.  
...
Section 3.9
Screen Failure
A screen failure subject is one from whom informed consent/assent 
(if applicable) is obtained and is documented in writing (ie, the 
subject’s parent or legal guardian signs an ICF or PIS), but who is 
not started on treatment, whether through randomization or open 
assignment.
Since the core component of this trial is a 6-month safety follow-up 
trial, no subject will be considered a screen failure. 
Section 3.10
Definition of 
Completed 
Subjects
The observation period is defined as the time period during which 
subjects are evaluated for primary and/or secondary objectives of 
the trial irrespective of whether or not the subject was on tolvaptan 
treatment.  Subjects who are evaluated at the last scheduled visit 
during the observation period will be defined as trial completers.  
The core safety follow-up component of the trial is defined as the 
time period during which subjects are evaluated for primary and/or 
secondary objectives of the trial regardless of whether or not the 
subject was on tolvaptan treatment.  Subjects who are evaluated at 
the last scheduled visit during the core safety follow-up component 


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For purposes of this trial, subjects who complete the Month 6 Visit 
will be defined as trial completers.  Any visits beyond the Month 6 
Visit will be considered “follow-up” visits for the purpose of 
evaluating safety and efficacy for those subjects who require 
continued treatment with tolvaptan.
Prior to the end of the trial, the sites should document each subject’s 
final visit, including the date of the last dose and the number of 
treatment cycles.
will be defined as trial completers.  For purposes of this trial, 
subjects who complete the Month 6 visit will be defined as trial 
completers.  Any visits beyond the Month 6 Visit will be considered 
“follow-up” visits for the purpose of evaluating safety and efficacy 
for those subjects who require treatment with tolvaptan.
Prior to the end of the trial, each subject’s final visit should be 
documented, including the date of the last dose and the number of 
treatment cycles.
Section 3.11
Definition of 
Lost to Follow-
up
Subjects or subjects’ parents/guardians who cannot be contacted on 
or before their final visit prior to the trial termination date, who do 
not have a known reason for discontinuation (eg, withdrew consent 
or AE), and for whom a current health status at the end of the trial 
cannot be determined will be classified as “lost to follow-up” as the 
reason for discontinuation.  Current health status can be determined 
from a variety of sources, either by obtaining acceptable 
documentation for death (ie, death certificate, medical records, 
public records, or statement by a family member or primary care 
physician) or acceptable documentation for life (ie, direct contact 
with the subject, medical records, successful telephone contact with 
the subject, statement by a family member or primary care 
physician, or public records).  It is expected that 3 documented 
attempts will be made to determine a subject’s current health status 
before assigning a “lost to follow-up” status.
Subjects or subjects’ parents/guardians who cannot be contacted on 
or before their final visit prior to the trial termination date, who do 
not have a known reason for discontinuation (eg, withdrew consent 
or AE), and for whom a current health status at the end of the trial 
cannot be determined will be classified as “lost to follow-up” as the 
reason for discontinuation.  Current health status can be determined 
from a variety of sources, either by obtaining acceptable 
documentation for death (ie, death certificate, medical records, 
public records, or statement by a family member or primary care 
physician) or acceptable documentation for life (ie, direct contact 
with the subject, medical records, successful telephone call with the 
subject, statement by a family member or primary care physician, or 
public records).  It is expected that 3 documented attempts will be 
made to determine a subject’s current health status before assigning 
a “lost to follow-up” status.
Section 3.12
Subject 
Compliance
Compliance will be ensured by watching the subject take his/her 
trial medication while the subject is hospitalized or during clinic 
visits.  For nonclinic days, compliance will be assessed by the 
number of tablets remaining when the subject returns the blister 
cards at the next visit. This information will be recorded on the 
appropriate CRF and on the Drug Accounting Form.
For the Core Safety Follow-up Component compliance is defined as 
completion of all visits.
For the Optional Tolvaptan Treatment Component compliance will 
be ensured by watching the subject take his/her tolvaptan while the 
subject is hospitalized or during clinical trial site visits.  For 
nonclinical trial site days, compliance will be assessed by the 
number of tablets remaining when the subject returns the blister 
cards at the next visit.  This information will be recorded on the 
appropriate CRF and on the Drug Accounting Form.
Section 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/assent process, IMP dispensing or subject dosing error, 
In the event of a significant deviation from the protocol because of 
an emergency, accident, or mistake (eg, violation of informed 
consent/assent process, tolvaptan dispensing or subject dosing error, 


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treatment assignment error, or 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.
treatment assignment error, or 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.
Section 4.2 Other 
Restrictions
The ingestion of pomelo, grapefruit, grapefruit juice, products 
containing Seville oranges, and St. John’s Wort is prohibited from 
72 hours prior to dosing with tolvaptan until 24 hours post-last dose 
of IMP.  In addition, the use of alcohol within 72 hours prior to 
dosing and during tolvaptan treatment is prohibited.
The use of saline in this population should be closely monitored.  
The use of hypertonic saline (3% or greater) within 8 hours of the 
initial screening laboratory collection prior to tolvaptan treatment is 
prohibited.  The use of hypertonic saline (3% or greater) is highly 
discouraged during tolvaptan treatment.  Please see Section 3.2.4 
for the list of prohibited medications during tolvaptan treatment.  
The use of normal saline (0.9%) is allowed during the Pretreatment 
Baseline Period until the beginning of treatment; normal saline use 
can resume during the follow-up period.  Subjects should no longer 
be on maintenance fluids containing normal saline during treatment 
with tolvaptan.  Subjects may be administered IV solutions 
containing hypotonic saline (eg, half-normal [0.45%] saline) if 
necessary, for fluid management.  The medical monitor should be 
contacted at any point if questions arise regarding the use of saline 
during the trial.
The ingestion of pomelo, grapefruit, grapefruit juice, products 
containing Seville oranges, and St. John’s Wort is prohibited from 
72 hours prior to dosing with tolvaptan until 24 hours post-last dose 
of tolvaptan.  In addition, the use of alcohol within 72 hours prior to 
dosing and during tolvaptan treatment is prohibited.
The use of saline in this population should be closely monitored.  
The use of hypertonic saline (3% or greater) within 8 hours of the 
initial screening laboratory collection prior to tolvaptan treatment is 
prohibited.  The use of hypertonic saline (3% or greater) is highly 
discouraged during tolvaptan treatment.  Please see Section 4.1 for 
the list of prohibited medications during tolvaptan treatment.  The 
use of normal saline (0.9%) is allowed during the Pretreatment 
baseline Period until the beginning of treatment; normal saline use 
can resume during the follow-up period.  Subjects should no longer 
be on maintenance fluids containing normal saline during treatment 
with tolvaptan.  Subjects may be administered IV solutions 
containing hypotonic saline (eg, half-normal [0.45%] saline) if 
necessary, for fluid management.  The medical monitor should be 
contacted at any point if questions arise regarding the use of saline 
during the trial.
Section 5.1 
Definitions
An AE is defined as any new untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related.
...

Pregnancies are also defined as IREs.  Although normal 
pregnancy is not an AE, it will mandate IMP 
discontinuation and must be reported on an IRE form to 
OPDC.  Pregnancy will only be documented on the AE 
CRF if there is an abnormality or complication.
An AE is defined as any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug 
related.
...
Pregnancies are also defined as IREs, although normal pregnancy is 
not an AE, it will mandate IMP discontinuation and must be 
reported on an IRE form to OPDC.  Pregnancy will only be 
documented on the AE CRF if there is an abnormality or 
complication.


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...
IMP Causality:  Assessment of causal relationship of an AE to the 
use of the IMP:
Related:
There is a reasonable possibility of a causal 
relationship.
Possibly related:
There is a reasonable causal relationship 
between the IMP and the AE.  Dechallenge is 
lacking or unclear.
Unlikely related:
There is a temporal relationship to IMP 
administration, but there is not a reasonable 
causal relationship between the IMP and the 
AE.
Not Related:
There is no temporal or reasonable relationship 
to the IMP administration.
...
IMP Causality:  Assessment of causal relationship of an AE to the 
use of the IMP:
Related:
There is a reasonable probability or possibility 
of a temporal and causal relationship between 
the study drug and the AE.
Not Related:  
There is no temporal or causal relationship to 
the study drug administration.
Section 5.2 
Eliciting and 
Reporting 
Adverse Events
The investigator will periodically assess subjects for the occurrence 
of AEs.  In order to avoid bias in eliciting AEs, subjects should be 
asked the following nonleading question: "How have you felt since 
your last visit?"  All AEs (serious and non-serious) reported by the 
subject must be recorded on the source documents and CRFs 
provided by the sponsor.
...
The investigator will periodically assess subjects for the occurrence 
of AEs.  In order to avoid bias in eliciting AEs, subjects should be 
asked the following non-leading question:  “How have you felt since 
yesterday/last time we spoke?”  All AEs (serious and non-serious) 
reported by the subject must be recorded on the source documents 
and CRFs provided by the sponsor.
...
Section 5.3 
Immediately
Reportable 
Events
...
Non-serious events that require discontinuation of IMP (including 
laboratory abnormalities) should be reported to INC Research
within 3 working days.  The IRE form must be completed and sent 
by fax or overnight courier to the sponsor.
...
...
Non-serious events that require discontinuation of tolvaptan 
(including laboratory abnormalities) should be reported to INC 
Research within 3 working days.  The IRE form must be completed 
and sent by fax or overnight courier to the sponsor.
...
Section 5.3.1.1 
Rapid Correction 
of Serum Sodium
When tolvaptan is not administered with adequate fluid intake, 
overly rapid correction of serum sodium may occur.  Rapid 
correction of serum sodium may lead to osmotic demyelination 
syndrome, a condition that can lead to severe brain damage and 
even death.  Age-appropriate neurological examinations will be 
performed during administration of tolvaptan to monitor changes in 
health status in addition to serum sodium.  This protocol is designed 
to provide adequate vigilance during the administration of tolvaptan 
to ensure that over rapid correction does not occur in this pediatric 
When tolvaptan is not administered with adequate fluid intake, 
overly rapid correction of serum sodium may occur.  Rapid 
correction of serum sodium level may lead to osmotic 
demyelination syndrome, a condition that can lead to severe brain 
damage and even death.  Age-appropriate neurological examinations 
will be performed during administration of tolvaptan to monitor 
changes in health status in addition to serum sodium.  This protocol 
is designed to provide adequate vigilance during the administration 
of tolvaptan to ensure that overly rapid correction does not occur in 


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population.
Rapid correction of hyponatremia is defined as any increase in 
serum sodium 12 mmol/L/24 hours.  If this change is observed 
during the trial, it should be reported as an IRE following the 
instructions detailed in Section 5.3 of the protocol.
this pediatric population.
Rapid correction of hyponatremia is defined as any increase in 
serum sodium 12 mEq/L (mmol/L)/24 hours.  If this change is 
observed during the trial, it should be reported as an Immediately 
Reported Event (IRE) following the instructions detailed in 
Section 5.3.
Section 5.3.1.2 
Other 
Hyponatremia-
related Adverse 
Event
Other events related to hyponatremia should be monitored closely 
and reported as appropriate depending on their severity:

Absolute serum sodium level 145 mmol/L

Any increase in serum sodium > 8 mmol/L over a 10-hour 
period

Neurological symptoms or other signs or symptoms 
suggestive of osmotic demyelination

Worsening symptoms of hyponatremia

Hypovolemia or hypotension requiring intervention
...
Other events related to hyponatremia should be monitored closely 
and reported as appropriate depending on their severity:

Absolute serum sodium level 145 mEq/L

Any increase in serum sodium > 8 mEq/L [mmol/L] over a 
10-hour period

Neurological symptoms or other signs or symptoms 
suggestive of osmotic demyelination

Worsening symptoms of hyponatremia

Hypovolemia or hypotension requiring intervention
...
Section 5.4 
Potential Hy’s 
Law Cases
For a subject who experiences an elevation in AST or ALT that is 
3 ULN or whose levels increase 3 times their initial baseline 
value, a total bilirubin level should also be evaluated.  If the total 
bilirubin is 2 ULN or 2 times their baseline value, an IRE 
form should be completed with all values listed and also should be 
reported as an AE on the CRFs.
...
The definition of Hy’s Law laboratory criteria is provided in 
Section 1.3. To err on the side of caution, Otsuka decided to set a 
lower threshold for identification of potential Hy’s Law cases.  For a 
subject who experiences an elevation in AST or ALT that is 
2 ULN or whose levels increase 2 times their initial baseline 
value, a BT level should also be evaluated.  Elevated values should 
be confirmed via retest.  If the BT is 2 ULN or 2 times their 
baseline value, an IRE form should be completed with all values 
listed and also should be reported as an AE on the CRFs.
...
Section 5.4.1 
Liver 
Transaminase 
Elevations
Management of abnormal liver function test results should be based 
on the investigator’s clinical judgment.  A liver function test result 
that is 3 ULN is generally accepted as a medically significant 
occurrence across various medical cultures.
For a subject that experiences an elevation in AST or ALT that is 
3 ULN or whose levels increase 3 times their initial baseline 
value in subjects with an elevated baseline value, a total bilirubin 
Management of abnormal liver function test results should be based 
on the investigator’s clinical judgment.  A liver function test result 
that is 2 ULN is generally accepted as a medically significant 
occurrence across various medical disciplines.
For a subject that experiences an elevation in AST or ALT that is 
2 ULN or whose levels increase 2 times their initial baseline 
value in subjects with an elevated baseline value, a BT level should 


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level should also be evaluated.  If the total bilirubin is 2 ULN or 
2 times their baseline value in subjects with an elevated baseline 
value, an IRE form with all values listed should be completed and 
also reported as an AE on the CRFs.
The following guideline for repeat testing may be used by 
investigators as a reference for any subject with an ALT or AST 
3 ULN:
1)
ALT, AST, alkaline phosphatase, and total bilirubin should 
be repeated within 48 to 72 hours (needed to confirm 
abnormalities and determine if they are increasing or 
decreasing).
2)
Inquiries should be made about symptoms (fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, 
and/or rash).
...
2)
The frequency of retesting can decrease to once a week or 
less if abnormalities stabilize or if the trial drug has been 
interrupted/discontinued and the subject is asymptomatic.
also be evaluated.  If the BT is 2 ULN or 2 times their 
baseline value in subjects with an elevated baseline value, an IRE 
form with all values listed should be completed and also reported as 
an AE on the CRFs.
The following guideline for repeat testing may be used by 
investigators as a reference for any subject with an ALT or AST 
2 ULN:
1)
ALT, AST, alkaline phosphatase, and BT should be 
repeated within 48 to 72 hours (needed to confirm 
abnormalities and determine if they are increasing or 
decreasing).
2)
Inquiries should be made about symptoms (fatigue, 
nausea, vomiting, right upper quadrant pain or 
tenderness, fever, and/or rash) and signs like jaundice, 
yellowish discoloration of sclera, etc.
...
2)
Frequency of retesting can decrease to once a week or 
less if abnormalities stabilize or if the trial drug has 
been interrupted/discontinued and the subject is 
asymptomatic.
Section 5.4.1.1 
Criteria for 
Discontinuation 
From the 
Optional 
Tolvaptan 
Treatment 
Component of 
the Trial due to 
Liver 
Transaminase 
Elevations
Section 5.4.1.1 Criteria for Discontinuation From the Trial due 
to Liver Transaminase Elevations
A subject must be discontinued from the trial on confirmation of 
any of the following criteria:
1)
ALT or AST 8 ULN
2)
ALT or AST 5 ULN for more than 2 weeks
3)
ALT or AST 3 ULN AND (total bilirubin 2 ULN 
or INR > 1.5)
4)
ALT or AST 3 ULN with appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%)
If there is any question about how to proceed with a particular 
subject’s case, do not hesitate to contact your regional medical 
Section 5.4.1.1 Criteria for Discontinuation From the Optional 
Tolvaptan Treatment Component of the Trial due to Liver 
Transaminase Elevations
A subject must be discontinued from tolvaptan treatment on 
confirmation of any of the following criteria:
1)
ALT or AST 8 ULN
2)
ALT or AST 5 ULN for more than 2 weeks
3)
ALT or AST 3 ULN AND (BT 2 ULN or INR 
> 1.5)
4)
ALT or AST 3 ULN with appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (> 5%) and 
signs of jaundice


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monitor to discuss.  The FDA has issued a guidance for industry 
regarding this topic.  This guidance is not specific to hyponatremia.  
Otsuka is integrating many of the recommendations in this guidance 
into all of its clinical research programs.  For a link to this guidance 
along with up-to-date information from the FDA regarding drug-
induced liver injury please use the following internet addresses:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulat
oryInformation/Guidances/UCM174090.pdf
http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/ucm071
471.htm
If there is any question about how to proceed with a particular 
subject’s case, do not hesitate to contact your regional medical 
monitor to discuss it.  The FDA has issued a guidance for industry 
regarding this topic.  This guidance is not specific to hyponatremia.  
Otsuka is integrating many of the recommendations in this guidance 
into all of its clinical research programs.  Links to this guidance and 
information from the FDA regarding drug-induced liver injury are 
provided in the references.22,23
Section 5.5 
Pregnancy
Female subjects of childbearing potential who are sexually active 
must use an effective method of birth control during tolvaptan 
treatment and for 14 days after the last dose of IMP in a manner 
such that risk of failure is minimized.  Unless the subject or her 
partner(s) is sterile (ie, female subjects who have had a bilateral 
oophorectomy and/or hysterectomy; or male partners who have had 
a bilateral orchiectomy) or remains abstinent, two of the following 
precautions must be used:  vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth control pills, birth control 
depot injection, birth control implant, condom, or sponge with 
spermicide.  Any single method of birth control, including 
vasectomy and tubal ligation, may fail, leading to pregnancy.
Before enrolling female subjects of childbearing potential in this 
clinical trial, investigators must review guidelines about trial 
participation for female subjects of childbearing potential.  The 
topics should generally include:

General information

ICF/assent form, as applicable

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Prior to trial enrollment, female subjects of childbearing potential 
Female subjects of childbearing potential who are sexually active 
must use an effective method of birth control during the course of 
the trial and for 14 days after the last dose of IMP in a manner such 
that risk of failure is minimized.  Unless the subject or her partner(s) 
is sterile (ie, female subjects who have had an oophorectomy and/or 
hysterectomy; or male partners who have had orchiectomy) or 
remain abstinent, two of the following precautions must be used:  
vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, 
birth control pills, birth control depot injection, birth control 
implant, condom, or sponge with spermicide.  Any single method of 
birth control, including vasectomy and tubal ligation, may fail, 
leading to pregnancy.
Before enrolling female subjects of childbearing potential in this 
clinical trial, investigators must review guidelines about trial 
participation for female subjects of childbearing potential.  The 
topics should generally include:

General information

ICF/assent form, as applicable

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy


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must be advised of the importance of avoiding pregnancy during 
trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject’s parent or legal guardian must sign an ICF 
stating that the above-mentioned risk factors and the consequences 
were discussed with the subject and her parent/guardian.
During the trial, all female subjects of childbearing potential should 
be instructed to contact the investigator immediately if they suspect 
they might be pregnant (eg, missed or late menstrual cycle).
If a subject or investigator suspects that a female subject may be 
pregnant prior to IMP administration, the IMP administration must 
be withheld until the results of serum pregnancy tests are available.  
If the pregnancy is confirmed, the subject must not receive the IMP 
and must not be enrolled in the trial.  If pregnancy is suspected 
while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential 
withdrawal risks) until the result of the pregnancy is known.  If 
pregnancy is confirmed, the IMP will be permanently discontinued 
in an appropriate manner (eg, dose tapering if necessary for subject 
safety) and the subject withdrawn from the trial.  (Exceptions to trial 
discontinuation may be considered for life-threatening conditions 
only after consultations with the trial medical monitor.)
The investigator must immediately notify INC Research of any 
pregnancy associated with IMP exposure during the trial and for at 
least 14 days after the last dose of IMP and record the event on the 
IRE form and forward it to INC Research.  INC Research will 
forward the Pregnancy Surveillance Form(s) for monitoring the 
outcome of the pregnancy.
Protocol-required procedures for trial discontinuation and follow-up 
must be performed on the subject unless contraindicated by 
pregnancy (eg, x-ray studies).  Other appropriate pregnancy follow-
up procedures should be considered if indicated.  In addition, the 
investigator must report to INC Research, on appropriate Pregnancy 
Surveillance form(s), follow-up information regarding the course of 
the pregnancy, including perinatal and neonatal outcome.  Infants 
Prior to trial enrollment, female subjects of childbearing potential 
must be advised of the importance of avoiding pregnancy during 
trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject’s parent or legal guardian must sign an ICF 
stating that the above-mentioned risk factors and the consequences 
were discussed with the subject and parent/guardian.
During the trial, all female subjects of childbearing potential should 
be instructed to contact the investigator immediately if they suspect 
they might be pregnant (eg, missed or late menstrual cycle).
If a subject or investigator suspects that the subject may be pregnant 
prior to IMP administration, the IMP administration must be 
withheld until the results of serum pregnancy tests are available.  If 
the pregnancy is confirmed, the subject must be withdrawn from the 
trial.  If pregnancy is suspected while the subject is taking IMP, the 
IMP must be withheld immediately (if reasonable, taking into 
consideration any potential withdrawal risks) until the result of the 
pregnancy is known.  If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety) and the subject will be 
withdrawn from the trial.  (Exceptions to trial discontinuation may 
be considered for life-threatening conditions only after consultations 
with the trial medical monitor.)
The investigator must immediately notify INC Research of any 
pregnancy associated with IMP exposure, including 14 days after 
the last dose of IMP and record the event on the IRE form and 
forward it to INC Research.  INC Research will forward Pregnancy 
Surveillance Form(s) for monitoring the outcome of the pregnancy.
Protocol-required procedures for trial discontinuation and follow-up 
must be performed on the subject unless contraindicated by 
pregnancy (eg, x-ray trials).  Other appropriate pregnancy follow-up 
procedures should be considered if indicated.  In addition, the 
investigator must report to INC Research, on appropriate Pregnancy 
Surveillance form(s), follow-up information regarding the course of 
the pregnancy, including perinatal and neonatal outcome.  Infants 


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will be followed for a minimum of 6 months.
will be followed for a minimum of 6 months.
Section 5.7 
Follow-up of 
Adverse Events
For this trial, information on AEs will be followed until the Month 6 
Visit or for up to 7 days after the last dose of IMP, whichever is 
later.
For subjects in the core safety follow-up component of this trial, 
information on AEs will be followed until the Month 6 Visit. For 
subjects who receive tolvaptan in the optional tolvaptan treatment 
component of this trial, information on AEs will be followed for 
14 days after administration of the last dose of tolvaptan, with an in-
person visit at 7 post-last dose and 14 days post-last dose by 
telephone call.
Section 5.7.1 
Follow-up of 
Non-serious 
Adverse Events
Non-serious AEs that are identified on the last scheduled contact 
must be recorded on the AE CRF with the current status noted.  All 
non-serious events that are ongoing at this time will be recorded as 
ongoing on the CRF.
Non-serious AEs that are identified on the last scheduled contact 
must be recorded on the AE CRF with the current status noted.  If a 
subject has not recovered from and AE, follow-up visits must be 
scheduled until the AE is resolved or has stabilized without 
expectation of further improvement.  Visits can be scheduled at a 
reasonable frequency for the AEs being followed, eg, every 
7-28 days.  In order to characterize or exclude possible drug-related 
safety issues, additional laboratory or other procedures may be 
requested.  These data should be shared with the sponsor in the 
same confidential manner as the on-study data.  All non-serious 
events that are ongoing at this time will be recorded as ongoing on 
the CRF.  During data 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).
Section 5.7.2 
Follow-up of 
Post Trial 
Serious Adverse 
Events
...
This trial requires that subjects be actively monitored for SAEs until 
the Month 6 Visit or up to 7 days after the last dose of IMP, 
whichever is later.
...
This trial requires that subjects be actively monitored for SAEs until 
the Month 6 Visit or up to 14 days after the last dose of tolvaptan, 
whichever is later.


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Section 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 INC Research.  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 serious related AEs identified after 
the last scheduled contact until the events are resolved, or the 
subject is lost to follow-up.  The investigator should continue to 
report any significant follow-up information to INC Research up to 
the point the event has been resolved.
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 tolvaptan, 
should be reported to INC Research.  This may include SAEs that 
are captured on follow-up telephone call or at any other time point 
after the defined trial period (ie, up to last scheduled contact).  The 
investigator should follow serious related AEs identified after the 
last scheduled contact until the events are resolved, or the subject is 
lost to follow-up.  The investigator should continue to report any 
significant follow-up information to INC Research up to the point 
the event has been resolved.
Section 6.1 
Pharmacokinetic 
Analysis
For those subjects undergoing chronic treatment with tolvaptan for 
at least 8 consecutive weeks for each initiation or reinitiation of 
therapy, the concentration of tolvaptan and metabolites will be 
obtained and summarized using descriptive statistics.
For those subjects undergoing chronic treatment with tolvaptan for 
at least 8 consecutive weeks for each initiation or reinitiation of 
therapy, the concentration of tolvaptan and metabolites will be 
obtained and summarized using descriptive statistics.
Section 7.1 
Sample Size
Sample size was not determined by a formal computation to achieve 
a target power.  It is expected that approximately 140 subjects may 
enroll from previous tolvaptan pediatric trials for hyponatremia (ie, 
Trials 156-08-276, 156-12-205, and 156-13-207).
Sample size was not determined by a formal computation to achieve 
a target power.  It is expected that approximately 140 subjects may 
enroll from previous tolvaptan pediatric trials for hyponatremia (ie, 
Trials 156-08-276, 156-13-207, and 156-12-205).
Section 7.2 
Datasets for 
Analysis
The following datasets are defined for this trial:
Intent to Treat Dataset:  comprises all subjects for whom an ICF is 
signed for the trial.
Safety Dataset:  comprises those subjects who receive at least one 
dose of IMP.
Efficacy Dataset:  comprises those subjects in the Safety Dataset 
who have at least one post-baseline efficacy evaluation for serum 
sodium concentration.
The following datasets are defined for this trial:

Core Safety Follow-up Component

Core Dataset:  comprises all subjects for whom an ICF 
is signed for the trial.

Optional Tolvaptan Treatment Component

Safety Dataset:  comprises those subjects who receive 
at least one dose of tolvaptan.

Efficacy Dataset:  comprises those subjects in the 
Safety Dataset who have at least one post-baseline 
efficacy evaluation for serum sodium concentration.


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Section 7.4.1 
Primary 
Outcome 
Analysis
The following primary endpoints include:

AEs, including cases of dehydration

Vital signs

Body weight, height, and growth percentiles

Tanner Stages

Clinical laboratory abnormalities for subjects on tolvaptan:

Serum sodium, overly rapid changes in serum sodium

Changes from baseline in ALT and AST

Percentage of subjects with overly rapid improvement in 
serum sodium (12 mmol/L in 24 hours after the first dose 
at introduction or reintroduction of IMP)

Percentage of subjects who experience recurrence of 
hyponatremia while on IMP
A paired Student’s t-test will be used to evaluate growth data, eg, 
height, body weight, and growth percentiles.  Tanner Stages will be 
analyzed using the Cochran-Mantel-Haenszel row mean scores 
differ test controlling for subjects.
All other primary endpoints will be summarized using descriptive 
statistics.
The primary endpoint for all subjects participating in the Optional 
Tolvaptan Treatment Component of the trial is:

Change from baseline in serum sodium while tolvaptan is 
being administered by visit
Section 7.4.2 
Secondary 
Outcome 
Analyses
The secondary endpoint of this trial is the change in serum sodium 
from baseline at each visit while the IMP is being administered and 
will be analyzed by descriptive statistics.
The secondary endpoints for all subjects receiving tolvaptan in the 
Optional Tolvaptan Treatment Component of the trial include the 
following:

Percentage of subjects who require rescue therapy while on 
tolvaptan

Percentage of subjects requiring continuation of tolvaptan 
following 30 days of treatment

Percentage of subjects with overly rapid correction in 
serum sodium (12 mmol/L in 24 hours after the first dose 
at introduction or reintroduction of tolvaptan)

Changes from baseline in ALT, AST and BT


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In addition, the secondary endpoints for subjects participating in the 
Core Safety Follow-up Component of the trial include:

Frequency of AE reports

Change from baseline in QoL assessments (by visit)

Change from baseline in growth percentiles (by visit) for

body weight

body height

Tanner Staging progression score (at 6 months)

Change from baseline in serum sodium by visit
A paired Student’s t-test will be used to evaluate growth data, eg, 
body height and body weight percentiles.  Tanner staging will be 
analyzed using the Cochran-Mantel-Haenszel row mean scores 
differ test controlling for subjects.
All other endpoints will be summarized using descriptive statistics.
Section 7.4.3 
Exploratory 
Outcome 
Analyses
The exploratory outcome variable is Quality of Life assessments.  
This endpoint will be analyzed by descriptive statistics.
The exploratory outcome variables are changes from baseline for 
the neurocognitive battery assessments and will be summarized 
using descriptive statistics.
Section 7.5 
Analysis of 
Demographic 
and Baseline 
Charateristics
In general, baseline measurements of safety and efficacy variables 
are defined as their last measurements prior to the first dose of IMP.
Demographic characteristics and medical history at Baseline will be 
summarized by descriptive statistics, eg, proportion, mean, median, 
standard deviation, minimum, and maximum values.
Demographic characteristics and medical history at baseline will be 
summarized by descriptive statistics, eg, proportion, mean, median, 
standard deviation, minimum, and maximum values.
Section 7.6 
Safety Analyses
Safety variables to be analyzed include AEs, clinical laboratory 
data, and vital signs.  In general, summary statistics will be provided 
for safety variables based on all available data.
No text in this section


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Section 7.6.1 
Physical 
Examination and 
Vitals Signs Data
Section 7.6.1 Adverse Events
All AEs will be coded by Medical Dictionary for Regulatory 
Activities system organ class and preferred term.  The incidence of 
the following events will be summarized:
a) TEAEs by severity
b) Potentially drug-related TEAEs
c) TEAEs with an outcome of death
d) Serious TEAEs
e) Discontinuations due to TEAEs
Section 7.6.1 Physical Examination and Vitals Signs Data
In general, summary statistics for changes from baseline in vital 
signs will be provided.  Potentially clinically significant results in 
vital signs will also be summarized.  No analysis will be performed 
on physical examination data.  Physical examination data will be 
listed.  
Section 7.6.2 
Clinical 
Laboratory Data
Summary statistics for changes from baseline in the clinical 
laboratory measurements will be provided.  Potentially clinically 
significant results in laboratory tests will also be summarized.  Shift 
tables will be produced for assessing changes from baseline in 
clinical laboratory measurements in low-normal-high scale.  Where 
predose baseline values are unavailable, summary statistics of 
available data at each visit will be presented.
Summary statistics for changes from baseline in the clinical 
laboratory measurements will be provided.  Potentially clinically 
significant results in laboratory tests will also be summarized.  Shift 
tables will be produced for assessing changes from baseline in 
clinical laboratory measurements in low-normal-high scale.  Where 
baseline values are unavailable, summary statistics of available data 
at each visit will be presented.
Section 7.6.3 
Adverse Events
Section 7.6.3 Physical Examination and Vitals Signs Data
In general, summary statistics for changes from baseline in vital 
signs will be provided.  Potentially clinically significant results in 
vital signs will also be summarized.  No analysis will be performed 
on physical examination data.  Physical examination data will be 
listed.  Tanner Staging will be analyzed as described in 
Section 7.4.1.
Section 7.6.3 Adverse Events
All AEs will be coded by Medical Dictionary for Regulatory 
Activities system organ class and preferred term.  The incidence of 
the following events will be summarized for all subjects (AEs) and 
all subjects receiving tolvaptan (TEAEs):
1)
AEs and TEAEs by severity
2)
Potentially drug-related TEAEs
3)
AEs and TEAEs with an outcome of death
4)
Serious AEs and TEAEs
5)
Discontinuations due to AEs and TEAEs
Section 8.1 
Packaging and 
Labeling
The IMP will be provided to the investigator(s) by the sponsor (or 
designated agent).  The IMP will be supplied as 3.75-, 7.5-, 15-, and 
30-mg spray-dried tablets.  Each package used in the dosing period 
will be labeled to clearly disclose the subject ID, compound ID, trial 
number, the sponsor’s name and address, instructions for use, route 
of administration, appropriate precautionary statements, and other 
Tolvaptan will be provided to the investigator(s) by the sponsor (or 
designated agent).  Tolvaptan will be supplied as 3.75-, 7.5-, 15-, 
and 30-mg spray-dried tablets.  Each package used in the dosing 
period will be labeled to clearly disclose the subject ID, compound 
ID, trial number, the sponsor’s name and address, instructions for 
use, route of administration, appropriate precautionary statements, 


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information required by local regulatory authorities.
The current tolvaptan tablet formulation intended for use in this trial 
is limited to administration to those who can easily swallow a 3.75-
mg tablet (6 mm) and weigh 10 kg.  A suspension formulation is 
in development that will be suitable for children who cannot 
swallow tablets (eg, < 4 years) and will also allow dosage 
adjustment for children with body weight < 20 kg and who are 
taking any CYP3A4 inhibitors.  Once available, the protocol will be 
amended to include the details of this formulation.
and other information required by local regulatory authorities.
The current tolvaptan tablet formulation intended for use in this trial 
is limited to administration to those who can easily swallow a 3.75-
mg tablet (6 mm) and weigh 10 kg.  A liquid formulation is in 
development that will be suitable for children who cannot swallow 
tablets (eg, < 4 years) and will also allow dosage adjustment for 
children with body weight < 20 kg and who are taking any CYP3A4 
inhibitors.  Once available, the protocol will be amended to include 
the details of this formulation.
Section 8.2 
Storage
The IMP will be stored in a securely locked cabinet or enclosure.  
Access will be limited to the investigators and their designees.  
Neither investigators nor any designees may provide trial drugs to 
any subject not participating in this protocol.
The IMP will be stored at 25C (77F) or below, with excursions 
allowed from 15C to 30C (59F to 86F).  The clinical site staff or 
designated personnel will maintain a temperature log in the drug 
storage area recording the temperature at least once each working 
day.
Tolvaptan will be stored in a securely locked cabinet or enclosure.  
Access will be limited to the investigators and their designees.  
Neither investigators nor any designees may provide trial drugs to 
any subject not participating in this protocol.
Tolvaptan will be stored at 25C (77F) or below, with excursions 
allowed from 15C to 30C (59F to 86F).  The clinical trial site 
staff or designated personnel will maintain a temperature log in the 
drug storage area recording the temperature at least once each 
working day.
Section 8.3 
Accountability
The investigator, or designee, must maintain an inventory record of 
IMP received, dispensed, administered, and returned.
The investigator, or designee, must maintain an inventory record of 
tolvaptan received, dispensed, administered, and returned.
Section Returns 
and Destruction
Upon completion or termination of the trial, all unused and/or 
partially used IMP must be returned to OPDC (or a designated 
contractor).
All IMP returned to OPDC must be accompanied by the appropriate 
documentation and be clearly identified by protocol number and 
trial site number on the outermost shipping container.  Returned 
supplies should be in the original containers.  The assigned trial 
monitor should facilitate the return of unused and/or partially used 
IMP.
Upon completion or termination of the trial, all unused and/or 
partially used tolvaptan must be returned to OPDC (or a designated 
contractor).
All tolvaptan returned to OPDC must be accompanied by the 
appropriate documentation and be clearly identified by protocol 
number and trial site number on the outermost shipping container.  
Returned supplies should be in the original containers.  The 
assigned trial monitor should facilitate the return of unused and/or 
partially used tolvaptan.
Section 8.5.1 
Eliciting and 
Reporting 
Product Quality 
The investigator or designee must record all PQCs identified 
through any means from the receipt of the IMP from the sponsor 
through and including reconciliation and up to destruction, 
including subject dosing.  The investigator or designee must notify 
The investigator or designee must record all PQCs identified 
through any means from the receipt of tolvaptan from the sponsor 
through and including reconciliation and up to destruction, 
including subject dosing.  The investigator or designee must notify 


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Complaints
the sponsor (or sponsor’s designee) within 24 hours of becoming 
aware of the PQC by e-mail or telephone and according to the 
procedure outlined below.
...
the sponsor (or sponsor’s designee) within 24 hours of becoming 
aware of the PQC by e-mail or telephone and according to the 
procedure outlined below.
...
Section 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;

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, and duration of 
any AEs and the investigator's assessment of relationship 
to the 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 all clinicians who 
made an entry in the progress notes.
...
During each subject’s visit to the clinical trial site, 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;

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, and duration of 
any AEs and the investigator's assessment of relationship 
to tolvaptan 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 all clinicians who 
made an entry in the progress notes.
...
Section 9.4 
Records 
Retention at the 
Trial Site
Regulatory requirements for the archival of records for this trial 
necessitate that participating investigators maintain detailed clinical 
data for the longest of the following 3 periods:

A period of at least 2 years following the date on which 
approval to market the drug is obtained (or if IMP 
development is discontinued, the date of discontinuation); 
OR

A period of at least 3 years after the sponsor notifies the 
investigator that the final report has been filed with 
regulatory authorities; OR

Longer, region-specific storage requirements, if applicable.
The investigator 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 
Regulatory requirements for the archival of records for this trial 
necessitate that participating investigators maintain detailed clinical 
data for the longest of the following 3 periods:

A period of at least 2 years following the date on which 
approval to market the drug is obtained (or if tolvaptan 
development is discontinued, the date of discontinuation); 
OR

A period of at least 3 years after the sponsor notifies the 
investigator that the final report has been filed with 
regulatory authorities; OR

Longer, region-specific storage requirements, if applicable.
The investigator 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 


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investigator will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and 
data generated during this trial.  Such documentation is subject to 
inspection by the sponsor and relevant regulatory authorities.  If the 
investigator withdraws from the trial (eg, due to relocation or 
retirement), all trial-related records should be transferred to a 
mutually agreed upon designee within a sponsor-specified 
timeframe.  Notice of such transfer will be given to the sponsor in 
writing.
investigator will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and 
data generated during this trial.  Such documentation is subject to 
inspection by the sponsor and relevant regulatory authorities.  If the 
investigator withdraws from the trial (eg, because of relocation or 
retirement), all trial-related records should be transferred to a 
mutually agreed upon designee within a sponsor-specified 
timeframe.  Notice of such transfer will be given to the sponsor in 
writing.
Section 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) 
will be allowed full access to inspect and copy the records.  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.
...
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) 
will be allowed full access to inspect and copy the records.  All 
supplies of tolvaptan, 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.
...
Section 13 
Amendment 
Policy
The investigator will not make any changes to this protocol without 
the sponsor’s prior written consent and subsequent approval by the 
IRB/IEC.  Any permanent change to the protocol, whether it be 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/IEC.  
Except for “administrative” or “non-substantial” amendments, 
investigators will wait for IRB/IEC approval of the amended 
protocol before implementing the change(s).  Administrative 
amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the 
quality or safety of 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/IEC 
notification within 5 working days.  The sponsor will submit 
protocol amendments to the applicable regulatory agencies.
The investigator will not make any changes to this protocol without 
the sponsor’s prior written consent and subsequent approval by the 
IRB/IEC.  Any permanent change to the protocol, whether it be 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/IEC.  
Except for “administrative” or “non-substantial” amendments, 
investigators will wait for IRB/IEC approval of the amended 
protocol before implementing the change(s).  Administrative 
amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the 
quality or safety of the tolvaptan tablets used in the trial.  A protocol 
change intended to eliminate an apparent immediate hazard to 
subjects should be implemented immediately, followed by IRB/IEC 
notification within 5 working days.  The sponsor will submit 
protocol amendments to the applicable regulatory agencies.


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...
...
Section 14 
References
...
13
OPC-41061 Investigator’s Brochure. Rockville (MD): 
Otsuka Pharmaceutical Development & 
Commercialization, Inc.; Edition 19. Otsuka Report, issued 
11 Jul 2013.
...
17
Moritz ML, Ayus JC. Preventing neurological 
complications from dysnatremias in children. Pediatr 
Nephrol. 2005;20:1687-1700.
...
13
OPC-41061 Investigator’s Brochure. Rockville (MD): 
Otsuka Pharmaceutical Development & 
Commercialization, Inc.; Edition 20. Otsuka Report, issued 
11 Jul 2014.
...
17
Moritz ML, Ayus JC. Preventing neurological 
complications from dysnatremias in children. Pedatr 
Nephrol. 2005;20:1687-1700.
...
22
U.S. Food and Drug Administration. Guidance for 
Industry. Drug-induced liver injury: premarketing clinical 
evaluation [report on the internet]. 2009 Jul [cited 15 Feb 
2014]; Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianc
eRegulatoryInformation/Guidances/UCM174090.pdf.
23
U.S. Food and Drug Administration. [available on the 
internet, last updated 22Jan2014; cited 14Feb2014]. 
Available from: http://www.fda.gov/Drugs/ 
ScienceResearch/ResearchAreas/ucm071471.htm
Appendix 1 
Names of 
Sponsor 
Personnel
Report Immediately Reportable Events (serious adverse events, 
potential Hy’s Law cases, pregnancies, and adverse events requiring 
discontinuation of trial drug) to INC Research as follows:
Country
Safety Fax Numbers
United States 
 (primary) or 
 (alternative)
Argentina
Australia
Belgium
Canada 
 (primary) or 
 (alternative)
Columbia
Czech Republic
Report Immediately Reportable Events (serious adverse events, 
potential Hy’s Law cases, pregnancies, and adverse events requiring 
discontinuation of IMP) as follows:
Country
Safety Fax Numbers
Australia
Belgium
Canada 
 (primary) or 
 (alternative)
Czech 
Republic
Germany
Italy
PPD
PPD
PPD
PP
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Finland
France
Georgia
No toll free number available; please 
dial 
 (primary) or 
 (alternative)
Germany
Hong Kong
Israel
Italy
Korea
Latvia
Malaysia
Mexico
Netherlands
Philippines
Peru
Poland
Romania
Russia
Serbia
Singapore
South Africa
Spain
Taiwan
Thailand
Turkey
No toll free number available; please 
dial 
 (primary) or 
 (alternative)
Ukraine
United Kingdom
Medical Monitors:
Primary:
Netherlands
Peru
Poland
Romania
Spain
Turkey
No toll free number available;  
please dial 
 
(primary) or 
 
(alternative)
United 
Kingdom
United States
 (primary) or 
(alternative)
Project Leader/Medical Director:
Phone 
 Fax 
Clinical Management:
Phone 
 Fax 
Phone 
 Fax 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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 INC Research
3201 Beechleaf Court, Suite 600
Raleigh, North Carolina 27604 US
Phone 
 Mobile 
E-Mail 
Back-up:
 INC Research
580 Union Square Drive
New Hope, Pennsylvania 18938 US
Phone 
 Mobile 
E-Mail 
Europe/Rest of World:
 INC Research
Ul.Emaus 5
30-201 Krakow, Poland
Phone 
E-Mail 
Medical Director:
Phone 
 Fax 
Clinical Management:
 
Phone 
 Fax 
Phone 
 Fax 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Appendix 2 
Institutions 
Concerned With 
the Trial
Sponsor
Otsuka Pharmaceutical 
Development &
Commercialization, Inc.
2440 Research 
Boulevard
Rockville, Maryland 
20850, US
Phone:  
Medical Monitoring
INC Research
3201 Beechleaf Court, 
Suite 600
Raleigh, North Carolina 
27604-1547, US
Phone:  
Fax:  
Trial Management & 
Clinical Monitoring
INC Research
3201 Beechleaf Court, 
Suite 600
Raleigh, North Carolina 
27604-1547, US
Phone:  
Electronic Data 
Capture
MediData Solutions
79 Fifth Avenue, 8th 
Floor
New York, New York 
10003, US
Phone:  
Fax:  
Investigational 
Materials
Fisher Clinical Services
7554 Schantz Road
Allentown, 
Pennsylvania 18106, US
Study 
Communications & 
Patient/Site
Support
BBK Worldwide
117 Kendrick Street, 
Institutions concerned with this trial are:
Sponsor
Otsuka Pharmaceutical 
Development &
Commercialization, Inc.
2440 Research 
Boulevard
Rockville, Maryland 
20850, USA
Phone:  
Medical Monitoring
INC Research
3201 Beechleaf Court, 
Suite 600
Raleigh, North Carolina 
27604-1547, USA
Phone:  
Fax:  
Medical Monitor:
 
 INC Research
580 Union Square Drive
New Hope, 
Pennsylvania 18938 US
Phone 
 Mobile 
E-Mail 
Trial Management & 
Clinical Monitoring
INC Research
3201 Beechleaf Court, 
Electronic Data 
Capture
MediData Solutions
79 Fifth Avenue, 8th 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Phone:  
Fax:  
Suite 600
Needham, 
Massachusetts 02494, 
US
Phone:  
Central Laboratory 
(PK)
ICON Development 
Solutions, Inc.
8282 Halsey Road
Whitesboro, New York 
13492, US
Phone:  
Suite 600
Raleigh, North Carolina 
27604-1547, USA
Phone:  
Floor
New York, New York 
10003, USA
Phone:  
Fax:  
Investigational 
Materials
Almac Clinical Services 
Limited
Seagoe Industrial Estate
9 Charlestown Road
Craigavon
County Armagh
BT63 5PW
United Kingdom
Study 
Communications & 
Patient/Site
Support
Mathews Media Group 
700 King Farm 
Boulevard, Suite 500
Rockville, MD 20850, 
USA
Phone: 
IRT Systems 
(treatment 
assignment)
S-CLINICA
1500 Market Street
12th Floor East Tower
Philadelphia, 
Pennsylvania 19102, 
USA
Phone:  
Central Laboratory 
(PK)
ICON Development 
Solutions, Inc.
8282 Halsey Road
Whitesboro, New York 
13492, USA
Phone:  
Clinical Laboratory 
Supplies
Neurocognitive 
Battery
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Covance Central 
Laboratory Services
8211 SciCor Drive
Indianapolis, Indiana 
46214, USA
Phone:  
Cogstate, Ltd.
195 Church Street
8th Floor
New Haven, CT 
06510 USA
Phone:  
PPD
PPD


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Appendix 3 
Handling and 
Shipment of 
Bioanalytical 
Samples
All tubes must be labeled such that the protocol number, subject 
number, date of collection, and time can be verified.  The OPDC 
Bioanalytical Scientist must approve the labels, prior to use.  It is 
important to note the exact time of the blood collection on the CRF, 
not the scheduled time for the drawing.  The exact time of dosing 
should also be noted.
Plasma Samples for Tolvaptan
Blood (1 mL) will be collected into plastic Vacutainer tubes 
containing sodium heparin anticoagulant.  The tubes should be 
gently inverted 3 to 4 times and then centrifuged at 2,000 to 
3,000 rpm for at least 10 to 15 minutes at 4C.  The rpm should be 
kept at a constant setting throughout the trial.  Plasma should be 
stored at −20C or on dry ice.  Samples should be shipped monthly.
Shipment of Plasma
The label on each tube must correspond to the requisition sheet and 
must be firmly attached with transparent tape and should include the 
protocol number, subject number, date of collection, and sample 
protocol time elapsed postdose.  Samples must be neatly packed and 
retained in an insulated container (place container supplied within a 
cardboard box) with enough dry ice to last 72 hours (ie, at least 
15 to 20 pounds).  Boxes should be completely filled with dry ice to 
avoid air spaces that will allow evaporation of the dry ice.  The 
container should be sealed with tape and placed in a cardboard box.  
The recipient must be alerted of shipments.  Packages will not be 
shipped on Thursdays, Fridays, Saturdays, or any day prior to a 
holiday.  Shipments will be via an overnight carrier.
All tubes must be labeled using the central laboratory’s bar code 
labels provided with the sample collection kits. The central 
laboratory’s requisition form must be completely filled out in 
regards to all the sample information.  In addition, the subject ID 
number and date of collection must be hand-written on the sample 
tube. It is important to note the exact time of the blood collection 
on the eCRF.
Each specimen must be labeled using a waterproof pen. A label 
suitable for the storage conditions must contain the subject ID 
number and date of collection, must correspond to the requisition 
form, and must be firmly attached. The requisition form must 
contain the name, address, and telephone number of the contact 
person from the trial site.
Plasma Samples for Tolvaptan
Blood (1 mL) will be collected into plastic Vacutainer tubes 
containing lithium heparin anticoagulant.  The tubes should be 
gently inverted 3 to 4 times and then centrifuged at 2,000 to 
3,000 rpm for at least 10 to 15 minutes at 4C.  The rpm should be 
kept at a constant setting throughout the trial.  Plasma should be 
stored at −20C or on dry ice.  Samples should be shipped monthly.
Shipment of Plasma
Plasma samples must be neatly packed in the kits provided by the 
central laboratory and restrained in a Styrofoam container that is 
completely filled with dry ice to avoid air spaces that allow 
evaporation of the dry ice.  The Styrofoam container should be 
sealed with tape and placed in a cardboard box.  The central 
laboratory must be alerted of sample shipment.  Packages must not 
be shipped on Thursday, Fridays, Saturdays, or any day prior to a 
holiday without the expressed consent of OPDC or the central 
laboratory. Shipments from clinical trial sites will be via an 
overnight carrier to the central laboratory (Clinical Laboratory 
Supplies, Covance Central).


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Appendix 5 
Optional 
Tolvaptan 
Treatment 
Component:  
Eligibility 
Criteria
New section in this amendment
Subjects will be eligible for tolvaptan treatment if they meet the 
criteria outlined in the table below.
Eligibility Criteria for Optional Tolvaptan 
Treatment
1.
Male or female subjects 4 weeks (or 44 weeks 
adjusted gestational age) to < 18 years old
2.
The subject must have been off treatment with the 
investigational medicinal product (IMP) for 7 days 
following the end of treatment in the previous trial of 
titrated oral IMP (tolvaptan in Trial 156-08-276, tolvaptan 
or placebo in Trials 156-13-207 and 156-12-205) to assess 
the subject’s clinical need for dosing
3.
Persistent dilutional (euvolemic or hypervolemic 
hyponatremia) defined as being documented as present for 
at least 48 hours, evidenced by at least 2 serum sodium 
assessments < 130 mEq/L (mmol/L) drawn at least 
12 hours apart (these values can be documented using 
historical values previously obtained per standard of 
care); a third (STAT) serum sodium assessment < 130 
mEq/L (mmol/L), which will serve as the baseline value 
for efficacy endpoints, is to be obtained within 2 to 4 
hours prior to the first dose of tolvaptan
4.
Ability to take oral medication
5.
Ability to maintain adequate fluid intake whether orally or 
via IV support with adequate monitoring
6.
Ability to comply with all requirements of the trial
7.
Trial-specific written informed consent/assent obtained 
from a parent/guardian or legally acceptable 
representative, as applicable per age of subject or local 
laws, prior to the initiation of any protocol-required 
procedures.  In addition, the subject as required by local 
laws must provide informed assent at the pretreatment 
baseline for this trial and must be able to understand that


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he or she can withdraw from the trial at any time.  All 
informed consent/assent procedures must be in 
accordance with the trial center’s IRB/IEC and local 
regulatory requirements
8.
Ability to commit to remain abstinent or practice double-
barrier birth control during the trial and for 14 days 
following the last dose of tolvaptan for sexually active 
females of childbearing potential
Subjects will be ineligible for tolvaptan treatment if they meet any 
of the following criteria:
Ineligibility Criteria for Tolvaptan Treatment
1.
Has evidence of hypovolemia or intravascular volume 
depletion (eg, hypotension, clinical evidence of volume 
depletion, response to saline challenge); if the subject has 
systolic blood pressure or heart rate outside of the normal 
range for that age volume status should be specifically 
clinically assessed to rule out volume depletion.
2.
Has serum sodium < 120 mEq/L (mmol/L), with or 
without associated neurologic impairment (ie, symptoms 
such as apathy, confusion, or seizures)
3.
Use of potent CYP3A4 inhibitors in subjects 50 kg or 
moderate CYP3A4 inhibitors in subjects < 20 kg
4.
Lacks free access to water (inability to respond to thirst) 
or without ICU-level fluid monitoring and management
5.
Has a history or current diagnosis of nephrotic syndrome
6.
Has transient hyponatremia likely to resolve (eg, head 
trauma or post-operative state)
7.
Has hyperkalemia defined as serum potassium above the 
ULN for the appropriate pediatric age range
8.
Has eGFR < 30 mL/min/1.73 m2 calculated by the 
following equation:
eGFR (mL/min/1.73 m2) = 0.413 height (cm)/serum 


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creatinine (mg/dL)
9.
Has AKI defined as:

Increase in serum creatinine by 0.3 mg/dL (26.5 
mol/L) within 48 hours; or

Increase in serum creatinine to 1.5 times baseline, 
which is known or presumed to have occurred within 
the prior 7 days; or

Urine volume < 0.5 mL/kg/h for 6 hours
10
.
Has severe or acute neurological symptoms requiring 
other intervention (eg, hyperemesis, obtundation, 
seizures)
11
.
Has had treatment for hyponatremia with:

Hypertonic saline (including normal saline challenge) 
within 8 hours of qualifying serum sodium 
assessments;

Urea, lithium, demeclocycline, conivaptan, or 
tolvaptan within 4 days of qualifying serum sodium 
assessments;

Other treatment for the purpose of increasing serum 
sodium concurrent with dosing of trial medication
12
.
Has anuria or urinary outflow obstruction, unless the 
subject is, or can be, catheterized during the trial
13
.
Has a history of drug or medication abuse within 3 
months prior to the pretreatment visit or current alcohol 
abuse
14
.
Has a history of hypersensitivity and/or idiosyncratic 
reaction to benzazepine or benzazepine derivatives (such 
as benazepril)
15
.
Has psychogenic polydipsia (subjects with other 
psychiatric illness may be included per medical monitor 
approval)
16
.
Has uncontrolled diabetes mellitus, defined as fasting 
glucose > 300 mg/dL (16.7 mEq/L [mmol/L])


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17
.
Has screening liver function values > 3 ULN.  An IRE 
form will be completed if the subject is a potential Hy’s 
Law case (any increase of AST or ALT 2 ULN or 
baseline value with an increase in BT 2 ULN or 
baseline value).
18
.
Has deficient coagulation (eg, cirrhotic at risk of GI 
bleed), including subjects who meet any of the following 
criteria:  a major GI bleed within the past 6 months, 
evidence of active bleeding (eg, epistaxis, 
petechiae/purpura, hematuria, or hematochezia), platelet 
count < 50,000/L, or use of concomitant medications 
known to increase bleeding risk
19
.
Has hyponatremia due to the result of any medication that 
can safely be withdrawn (eg, thiazide diuretics)
20
.
Has hyponatremia (eg, hyponatremia in the setting of 
adrenal insufficiency, untreated hypothyroidism, or 
hypotonic fluid administration) that is most appropriately 
corrected by alternative therapies
21
.
Is currently pregnant or breastfeeding
22
.
Has any medical condition that, in the opinion of the 
investigator, could interfere with evaluation of the trial 
objectives or safety of the subjects.
23
.
Is deemed unsuitable for trial participation in the opinion 
of the investigator
24
.
Participation in an investigational drug trial (other than 
Trials 156-08-276, or 156-13-207 or 156-12-205) within 
the past 30 days, without prior approval from the medical 
monitor
25
.
Subjects <2 years of age, weight <10 kg, or who cannot 
swallow an oral tablet are excluded until an oral liquid 
formulation becomes available
AKI = acute kidney injury; eGFR = estimated glomerular filtration 
rate; GI = gastrointestinal; ICU = intensive care unit; IRE = 
Immediately Reportable Event; ULN = upper limit of normal


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Appendix 6 
Optional 
Tolvaptan 
Treatment 
Component: 
Laboratory 
Assessment 
Schedule
New section in this amendment
Frequency of Recurring Laboratory Assessments
Treatment 
Phase
Serum Sodium
LFTs 
(ALT, 
AST, BT)
PKa
Pretreatment 
Baseline doses
Day -1 to 
Day -4: 
assessments 
130 mEqL 
(mmol/L) 12 
hours apart
Month 1:  
Titrationb
Once daily
Month 1: 
Post-titrationc 
Once weekly 
Once 
monthly
Month 2: 
Post-titration 
(steady dose)
Every 2 weeks
Once 
monthly
Once post 
8 weeks of
continous
treatment
Month 3+ 
post-titration 
(steady dose): 
Maintenance
Once monthly
Once 
monthlyd,e
Month 6, End 
of Treatment 
or Early 
Termination
24 (4) hours 
and 7 (1) days
aOnce post 8 weeks for every new cycle of treatment
bDay 1 up to Day 4
cDays 7, 14, 21, and 28
dAST, ALT, and BT will be assessed if more than 1 month has 
elapsed since LFTs were performed


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eSee Section 3.7.5.3.1 for more information and Section 5.4 for 
detailed instructions on follow-up of subjects with elevations in 
AST, ALT, or BT that are 2 ULN or levels that increase 2 x 
from baseline.


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Amendment Number:
2
Issue Date:
26 February 2015
PURPOSE:

Implementation of additional serum sodium testing during drug titration to align 
with the current EU label (SmPC) for the adult indication of hyponatremia.  We 
are adding safety testing for serum sodium at interim time points during titration 
with the option of using a point of care device to minimize impact on total blood 
volume required for the trial.

Additional background data from non-clinical juvenile toxicity studies.

Updates to clarify prohibition of hypertonic saline.

Clarify roll-over into extension study 156-11-294. 

Clarification of scheduled treatment interruption after 30 days of treatment and 
close clinical monitoring with the addition of visits.
BACKGROUND:
This protocol is the safety follow-up study to all trials in the tolvaptan pediatric 
hyponatremia program and is required by the EU Paediatric Investigation Plan.
The study provides a mandatory 6 month safety follow-up for all subjects regardless of 
treatment status.  Those subjects who have a continued medical need for treatment have 
the opportunity to receive tolvaptan.
For all subjects the main focus is to provide information on the developmental impact and 
quality of life associated with tolvaptan therapy.  For those subjects who continue to 
receive treatment safety and efficacy of long-term treatment will be evaluated.
Updates have been made to address comments from the FDA, the Medicines and 
Healthcare Products Regulatory (MHRA), and other regulatory agencies.
MODIFICATIONS TO PROTOCOL:
Sectional Revisions:  changes made to specific sections of the protocol are listed in the 
table below.


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Title Page:
Issue Date:
31 October 2013
Date of Amendment 1:
5 September 2014
Issue Date:
31 October 2013
Date of Amendment 1:
5 September 2014
Date of Amendment 2:
26 February 2015
Protocol 
Synopsis 
Objectives:
This trial will consist of a core safety follow-up component 
(duration:  6 months) and an optional tolvaptan treatment 
component (duration:  variable, depending on the subjects’ 
continuing need for tolvaptan treatment). 
The objectives of this trial are:
The objective of this trial is to provide 6 months of safety follow-up for 
children who have participated in prior tolvaptan hyponatremia trials.  In 
addition, there is an option to receive continuing treatment of variable 
duration based on medical need.
Protocol 
Synopsis 
Subject 
Population:
Up to 140 male or female subjects may be eligible for this 
trial; subjects will need to have participated in one of the 
previous tolvaptan pediatric trials for dilutional (euvolemic 
or hypervolemic) hyponatremia (ie, Trials 156-08-276, 
156-13-207, or 156-12-205).
Approximately 140 male or female subjects may be eligible for this trial; 
subjects will need to have participated in one of the previous tolvaptan 
pediatric trials for dilutional (euvolemic or hypervolemic) hyponatremia 
(ie, Trials 156-08-276, 156-13-207, or 156-12-205).
Protocol 
Synopsis 
Inclusion/Exclu
sion Criteria:

Participation in one of the previous tolvaptan pediatric 
trials for hyponatremia (ie, Trials 156-08-276, 156-13-
207, or 156-12-205).

Enrollment in one of the previous tolvaptan pediatric trials for 
hyponatremia (ie, Trials 156-08-276, 156-13-207, or 156-12-205).
Protocol 
Synopsis Trial 
Sites:
Subjects may be enrolled at up to 65 clinical trial sites 
globally.
Subjects may be enrolled at approximately 75 clinical trial sites globally.
Investigational 
Medicinal 
Product, Dose, 
Formulation, 
Mode of 
Administration:
Subjects enrolled in this trial will not receive tolvaptan 
unless they demonstrate a clinical need as determined by 
the investigator and meet the eligibility criteria for 
treatment.
Tolvaptan will initially be supplied as 3.75-, 7.5-, 15-, and 
Subjects enrolled in this trial will not receive tolvaptan unless they 
demonstrate a clinical need as determined by the investigator and meet the 
eligibility criteria for optional tolvaptan treatment.
Tolvaptan will initially be supplied as 3.75-, 7.5-, 15-, and 30-mg 
spray-dried tablets.  Upon the availability of an alternate formulation, the 


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30-mg spray-dried tablets.  Upon the availability of an oral 
liquid formulation, the protocol will be amended to reflect 
additional dosing options.
protocol will be amended to reflect additional dosing options.
Protocol 
Synopsis Trial 
Assessments:
Safety:

Vital signs

Physical examinations

Body height and weight/Growth percentiles

Tanner Staging

Clinical laboratory tests:  Serum sodium 
assessments and liver function tests (alanine 
transaminase [ALT], aspartate aminotransferase 
[AST], and total bilirubin [BT])

Adverse event reporting
Efficacy:

Serum sodium concentration

Continued need for tolvaptan treatment after the 
first 30 days of treatment 

Quality of Life

Vital signs

Physical examinations

Body height and weight/Growth percentiles

Tanner Staging

Clinical laboratory tests:  Serum sodium assessments and liver 
function tests (alanine transaminase [ALT], aspartate 
aminotransferase [AST], and total bilirubin [BT])

Adverse event reporting

Continued need for tolvaptan treatment after the first 30 days of 
treatment 

Quality of Life
Protocol 
Synopsis 
Criteria for 
Evaluation:
Safety:

Percentage of subjects with overly rapid correction 
in serum sodium (12 mEq/L [mmol/L]) in 24 
hours after the first dose at introduction or 
reintroduction of tolvaptan)

Changes from baseline in ALT, AST, and BT for 
subjects on tolvaptan

Frequency of AE reports for all subjects

Changes from baseline in growth percentiles 
(weight and height) for all subjects
Safety:

Percentage of subjects with overly rapid correction in serum 
sodium (12 mEq/L [mmol/L]) in 24 hours after the first dose at 
introduction or reintroduction of tolvaptan

Changes from baseline in ALT, AST, and BT for subjects on 
tolvaptan

Frequency of AE reports for all subjects

Changes from baseline in growth percentiles (weight and height) 
for all subjects

Tanner Staging progression for all subjects


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
Tanner Staging progression for all subjects

Change from baseline in serum sodium concentration
Protocol 
Synopsis Trial 
Duration:
The core safety follow-up component of the trial is 
expected to continue until all enrolled subjects from Trials 
156-08-276, 156-13-207, or 156-12-205 have been 
followed for a minimum of 6 months.  For subjects in the 
optional tolvaptan treatment component, the length of 
participation for each individual subject will vary 
depending on duration of treatment required and the need 
for repeated treatments.  The opportunity to participate in 
the Optional Tolvaptan Treatment Component is planned to 
remain open until the last subject completes the Core Safety 
Follow-up Component.
The core safety follow-up component of the trial is expected to continue 
until all enrolled subjects from Trials 156-08-276, 156-13-207, or 156-12-
205 have been followed for 6 months.  For subjects in the optional 
tolvaptan treatment component, the length of participation for each 
individual subject will vary depending on duration of treatment required 
and the need for repeated treatments.  The opportunity to participate in the 
Optional Tolvaptan Treatment Component is planned to remain open until 
the last subject completes the Core Safety Follow-up Component.
List of 
Abbreviations 
and Definitions 
of Terms:
Addition of 3 terms: IDMC, MHRA, and WOCBC
Deletion of 1 term: PIS Patient Information Sheet
IDMC Independent Data Monitoring Committee
MHRA Medicines and Healthcare Products Regulatory
WOCBC Women of child-bearing potential
1 Introduction:
The United States (US) Food and Drug Administration 
(FDA) and the European Medicines Agency (EMA) have 
required that pediatric trials be conducted for tolvaptan for 
the indication of hyponatremia.  This trial is an extension 
trial to follow children and adolescent subjects who 
participated in a previous tolvaptan pediatric trial for 
hyponatremia.  In addition, this trial will allow continued 
access to tolvaptan to those subjects with a clinical need per 
the investigator’s discretion.
The United States (US) Food and Drug Administration (FDA) and the 
European Medicines Agency (EMA) have required that pediatric trials be 
conducted for tolvaptan for the indication of hyponatremia.  This trial is an 
extension trial to follow children and adolescent subjects who participated 
in a previous tolvaptan pediatric trial for hyponatremia for safety.  In 
addition, this trial will allow continued access to tolvaptan to those 
subjects with a clinical need per the investigator’s discretion.
1.1.1 Juvenile 
Toxicity Data:
A 1-week dose range-finding study was conducted in rat 
pups at 4 or 7 days of age and results showed tolvaptan to 
be lethal at 1,000 mg/kg/day and tolerable at 100 mg/kg/day 
A 1-week dose range-finding study was conducted in rat pups at 4 or 7 
days of age and results showed tolvaptan to be lethal at 1,000 mg/kg/day 
and tolerable at 100 mg/kg/day and lower.


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and lower.
In another study, male and female rat pups at 4 days of age were orally 
administered tolvaptan for 9 weeks at doses of 10, 30, and 100 mg/kg/day.  
Similar to the above study, pharmacologically mediated changes were 
noted in urine volume, water consumption, and urine electrolytes at all 
doses. Dilated renal pelvis considered to be attributable to increased urine 
volume during very early infancy was noted in males at 30 mg/kg/day and 
higher and females at 100 mg/kg/day.  Toxicities were noted at 100 
mg/kg/day, including death in one male, suppressed body weight gain and 
food consumption in males and females, and delayed balanopreputial 
separation and prolonged prothrombin time in males. Except for 
prolonged prothrombin time, all changes noted during the administration 
period showed reversibility after a 4-week recovery period. The no 
observed adverse effect level in both males and females was judged to be 
30 mg/kg/day.27
1.2.1 
Pharmacokineti
cs/Pharmacody
namics:
Since inception of the program, a total of 46 phase 1 trials 
have been completed with tolvaptan (as of 31 Mar 2014) in 
healthy subjects or special populations in Japan, the United 
Kingdom, China, Korea, Argentina, and the US.  One phase 
1 trial is ongoing.
Following IV dosing, the terminal-phase elimination half-
life (t 1/2,z) of tolvaptan is about 3 hours.  Following single 
oral tablet doses, the t1/2,z of tolvaptan increases with 
increasing dose with mean values around 3 hours for a 15-
mg dose and 12 hours for 120- to 480-mg doses.  Tolvaptan 
is very insoluble, with solubility being 0.00005 w/v% at 
25C and is pH independent.  At lower doses, tolvaptan is 
mostly absorbed from the upper GI tract so the decline of 
Since inception of the program, a total of 53 clinical pharmacology trials 
have been completed with tolvaptan (as of 11 Jul 2014) in healthy subjects 
or special populations in Japan, the United Kingdom, China, Korea, 
Argentina, and the US.  One phase 1 trial is ongoing.
In healthy subjects,following IV dosing, the terminal-phase elimination 
half-life (t 1/2,z) of tolvaptan is about 3 hours.  Following single oral tablet 
doses, the t1/2,z of tolvaptan   0.00005 w/v% at 25C and is pH 
independent.  At lower doses, tolvaptan is mostly absorbed from the upper 
GI tract so the decline of the terminal portion of the concentration curve 
reflects elimination process only.  With increasing dose, there is continued 
absorption of tolvaptan from the GI tract such that the rate of decline of 
the terminal portion of the concentration curve is reflective of both 


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the terminal portion of the concentration curve reflects 
elimination process only.  With increasing dose, there is 
continued absorption of tolvaptan from the GI tract such 
that the rate of decline of the terminal portion of the 
concentration curve is reflective of both absorption and 
elimination processes.27
The limited early absorption of tolvaptan is exemplified by 
the fact that the maximum (peak) plasma concentration 
(Cmax) values show less than dose proportional increases 
from 30 to 240 mg and then a plateau at doses from 240 to 
480 mg.  Despite the changes in tolvaptan absorption, 
tolvaptan AUC values increase proportionally with 
increasing dose and apparent clearance of drug from plasma 
after extravascular administration (CL/F) values are 
unchanged for single doses of 30 to 480 mg.27
Tolvaptan concentrations do not accumulate following once 
daily dosing.  Following 300-mg doses, Cmax and AUC 
during the dosing interval at steady state (AUC) were only 
4.2- and 6.4-fold higher, respectively, when compared with 
the 30-mg dose.  This indicates bioavailability decreases 
with increasing dose.  Mean (range) absolute bioavailability 
of tolvaptan when administered as a 30-mg tablet was 56% 
(42% to 80%).
Trials in subjects with hyponatremia secondary to liver 
disease showed that following a single oral dose, tolvaptan 
concentrations increase dose proportionally from 5 to 60 
absorption and elimination processes.27
The limited early absorption of tolvaptan is exemplified by the fact that 
the maximum (peak) plasma concentration (Cmax) values show less than 
dose proportional increases from 30 to 240 mg and then a plateau at doses 
from 240 to 480 mg.  Despite the changes in tolvaptan absorption, 
tolvaptan AUC values increase proportionally with increasing dose and 
apparent clearance of drug from plasma after extravascular administration 
(CL/F) values are unchanged for single doses of 30 to 480 mg.27
Tolvaptan concentrations do not accumulate following once daily dosing.  
Following 300-mg doses, Cmax and AUC during the dosing interval at 
steady state (AUC) were only 4.2- and 6.4-fold higher, respectively, when 
compared with the 30-mg dose.  This indicates bioavailability decreases 
with increasing dose.  Mean (range) absolute bioavailability of tolvaptan 
when administered as a 30-mg tablet was 56% (42% to 80%).
Trials in subjects with hyponatremia secondary to liver disease showed 
that following a single oral dose, tolvaptan concentrations increase dose 
proportionally from 5 to 60 mg.  The clearance following single oral doses 
of tolvaptan was independent of the dose and similar to clearance in 
healthy subjects.  Following multiple oral doses, tolvaptan concentrations 
accumulated 2-fold and clearance was decreased about 50%.27
Once a day dosage regimen trials in CHF subjects with extracellular 
volume expansion showed that tolvaptan concentrations increased less 
than proportionally with dose upon multiple dosing regimens (10, 15, 30, 
60, 90, and 120 mg once daily for 13 days) in this subject population.  The 
t1/2,z and CL/F were unchanged across dose groups.  Compared to healthy 
subjects, the disposition of tolvaptan is slower with longer t1/2,z (7.8 to 


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mg.  The clearance following single oral doses of tolvaptan 
was independent of the dose and similar to clearance in 
healthy subjects.  Following multiple oral doses, tolvaptan 
concentrations accumulated 2-fold and clearance was 
decreased about 50%.
Once a day dosage regimen trials in CHF subjects with 
extracellular volume expansion showed that tolvaptan 
concentrations increased less than proportionally with dose 
upon multiple dosing regimens (10, 15, 30, 60, 90, and 120 
mg once daily for 13 days) in this subject population.  The 
t1/2,z and CL/F were unchanged across dose groups.  
Compared to healthy subjects, the disposition of tolvaptan 
is slower with longer t1/2,z (7.8 to 11.1 hours) and smaller 
CL/F (0.9 to 3.3 mL/min/kg).  The Cmax was 2- to 2.5-fold 
greater than that of healthy subjects (at 60- and 90-mg 
doses).  The median volume of distribution following 
extravascular administration of tolvaptan ranged from 1 to 
2.5 L/kg and was not different from healthy subjects.
Tolvaptan is a weak substrate for cytochrome P450 (CYP) 
3A4 and has no inhibitory activity at CYP3A4.  Tolvaptan 
administration does not produce clinically significant 
changes in amiodarone, warfarin (or its 7-hydroxy and 10-
hydroxy metabolites), lovastatin, furosemide, or 
hydrochlorothiazide plasma concentrations.  Steady state 
digoxin concentrations were increased approximately 20% 
(as determined by AUC).
When administered with the potent CYP3A4 inhibitor 
11.1 hours) and smaller CL/F (0.9 to 3.3 mL/min/kg).  The Cmax was 2- to 
2.5-fold greater than that of healthy subjects (at 60- and 90-mg doses).  
The median volume of distribution following extravascular administration 
of tolvaptan ranged from 1 to 2.5 L/kg and was not different from healthy 
subjects.
Tolvaptan is a sensitive substrate for cytochrome P450 (CYP) 3A4 and 
has no inhibitory activity at CYP3A4.  Tolvaptan administration does not 
produce clinically significant changes in amiodarone, warfarin (or its 7-
hydroxy and 10-hydroxy metabolites), lovastatin, furosemide, or 
hydrochlorothiazide plasma concentrations.  Steady state digoxin 
concentrations were increased approximately 20% (as determined by 
AUC).
When administered with the potent CYP3A4 inhibitor ketoconazole, the 
ketoconazole + tolvaptan/tolvaptan alone ratio for tolvaptan mean Cmax
and AUC from time zero to infinity values were 3.48 and 5.40, 
respectively.  Therefore, a 4-fold reduction in tolvaptan dose is 
recommended when initiating tolvaptan therapy in subjects using potent 
CYP3A4 inhibitors and a 2-fold reduction in tolvaptan dose is 
recommended for subjects using moderate CYP3A4 inhibitors.  Lovastatin 
increases tolvaptan Cmax by approximately 20% but CL/F is unchanged.  
Tolvaptan Cmax and AUC calculated to the last observable concentration at 
time t (AUCt) are increased 1.9- and 1.6-fold, respectively, when tolvaptan 
is coadministered with grapefruit juice.  Following coadministration with 
600 mg once daily rifampin at steady state, tolvaptan Cmax and AUCt are 
decreased 83% and 87%, respectively.
When 30- or 60-mg tablet doses were given following a standard high-fat, 
high-calorie meal, no clinically significant differences in urine output 


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ketoconazole, the ketoconazole + tolvaptan/tolvaptan alone 
ratio for tolvaptan mean Cmax and AUC from time zero to 
infinity values were 3.48 and 5.40, respectively.  Therefore, 
a 4-fold reduction in tolvaptan dose is recommended when 
initiating tolvaptan therapy in subjects using potent 
CYP3A4 inhibitors and a 2-fold reduction in tolvaptan dose 
is recommended for subjects using moderate CYP3A4 
inhibitors.  Lovastatin increases tolvaptan Cmax by 
approximately 20% but CL/F is unchanged.  Tolvaptan Cmax
and AUC calculated to the last observable concentration at 
time t (AUCt) are increased 1.9- and 1.6-fold, respectively, 
when tolvaptan is coadministered with grapefruit juice.  
Following coadministration with 600 mg once daily 
rifampin at steady state, tolvaptan Cmax and AUCt are 
decreased 83% and 87%, respectively.
When 30- or 60-mg doses were given following a standard 
high-fat, high-calorie meal, no clinically significant 
differences in urine output were observed.
Tolvaptan increases urine excretion rate at concentrations 
around 20 ng/mL and maximal urine excretion rates are 
reached between 100 and 150 ng/mL.  A single oral dose 
trial in healthy subjects using doses from 60 to 240 mg 
showed that there were 1) no further increases in urine 
excretion rate with doses beyond 180 mg; 2) no further 
increases in zero to 24 hour urine excretion with doses 
beyond 180 mg; and 3) as dose was increased, increases in 
urine excretion were sustained over time.  Tolvaptan 
elevated electrolyte-free water clearance to a positive value, 
were observed.
Following multiple oral doses, the tolvaptan metabolite DM-4103 was 
found to accumulate.  This metabolite has no pharmacological activity and 
has shown an acceptable toxicity profile.  The metabolite has not been 
shown to accumulate in nonclinical toxicokinetic studies; however, in a 
26-week study in rats, DM-4103 plasma concentrations greater than those 
expected at the dose used in this trial revealed no evidence of time-
dependent toxicological effects.
Tolvaptan increases urine excretion rate at concentrations around 20 
ng/mL and maximal urine excretion rates are reached between 100 and
150 ng/mL.  A single oral dose trial in healthy subjects using doses from 
60 to 240 mg showed that there were 1) no further increases in urine 
excretion rate with doses beyond 180 mg; 2) no further increases in zero to 
24 hour urine excretion with doses beyond 180 mg; and 3) as dose was 
increased, increases in urine excretion were sustained over time.  
Tolvaptan elevated electrolyte-free water clearance to a positive value, 
increased serum sodium and plasma osmolality, and increased plasma 
AVP concentrations and renin activity, but no dose-related increases were 
observed for any other parameter.
Details of the currently available pharmacokinetic (PK)/pharmacodynamic 
(PD) data for the compound are available in the IB.


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increased serum sodium and plasma osmolality, and 
increased plasma AVP concentrations and renin activity, 
but no dose-related increases were observed for any other 
parameter.
Following multiple oral doses, the tolvaptan metabolite 
DM-4103 was found to accumulate.  This metabolite has no 
pharmacological activity and has shown an acceptable 
toxicity profile.  The metabolite has not been shown to 
accumulate in nonclinical toxicokinetic studies; however, in 
a 26-week study in rats, DM-4103 plasma concentrations 
greater than those expected at the dose used in this trial 
revealed no evidence of time-dependent toxicological 
effects.
Details of the currently available pharmacokinetic 
(PK)/pharmacodynamic (PD) data for the compound are 
available in the IB.
1.3 Known and 
Potential Risks 
and Benefits:
As of 31 Mar 2014, pooled exposure data are available 
from 88 trials, including 7201 subjects worldwide who 
were exposed to oral doses of tolvaptan.  The extent of 
exposure to oral tolvaptan by dose in the pooled database 
(N = 7201) comprises 3115 subjects in trials for heart 
failure, 511 subjects in trials for hyponatremia, 961 subjects 
in the pivotal long-term ADPKD trial, 270 subjects in short-
term trials for ADPKD or renal impairment, 391 subjects in 
trials for cardiac edema, 855 subjects in trials for hepatic 
edema, 37 subjects with renal impairment in a phase 1 trial, 
and 1061 healthy subjects in clinical pharmacology trials. 
As of 31 Mar 2014, pooled exposure data are available from 88 trials, 
including 7201 subjects worldwide who were exposed to oral doses of 
tolvaptan spray-dried tablets.  The extent of exposure to oral tolvaptan by 
dose in the pooled database (N = 7201) comprises 3115 subjects in trials 
for heart failure, 511 subjects in trials for hyponatremia, 961 subjects in 
the pivotal long-term ADPKD trial, 270 subjects in short-term trials for 
ADPKD or renal impairment, 391 subjects in trials for cardiac edema, 
855 subjects in trials for hepatic edema, 37 subjects with renal impairment 
in a phase 1 trial, and 1061 healthy subjects in clinical pharmacology 
trials. 
The most commonly reported TEAEs (by > 10% incidence and greater 


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The most commonly reported TEAEs (by > 10% incidence 
and greater than placebo) in healthy subjects treated with 
tolvaptan were thirst, pollakiuria, and headache.  Headache 
was the most commonly reported TEAE in the placebo 
subjects.
The hyponatremia program comprised 835 subjects from 
12 short-term trials involving either exclusive evaluation of 
subjects with hyponatremia (9 trials) or substantial 
subpopulations of subjects with hyponatremia (3 CHF 
trials).  The 511 subjects in the hyponatremia trials were 
exposed to oral tolvaptan doses ranging from 5 to 60 mg, 
for a total of 8339 days of exposure.  In the 9 hyponatremia
trials, the most commonly reported TEAEs (> 5% 
incidence) in the tolvaptan subjects were thirst, dry mouth, 
peripheral oedema, nausea, dizziness, fatigue, constipation, 
headache, ascites, diarrhoea, pollakiuria, asthenia, 
hypotension, pyrexia, and hypokalaemia.  The most 
commonly reported TEAEs (> 5% incidence) in the placebo 
subjects were peripheral oedema, diarrhoea, headache, 
ascites, vomiting, dyspnoea, nausea, and hypotension.  The 
IB provides a thorough review of the adverse events (AEs) 
experienced with this compound during clinical trials.
than placebo) in healthy subjects treated with tolvaptan were thirst, 
pollakiuria, and headache.  Headache was the most commonly reported 
TEAE in the placebo subjects.
The hyponatremia program comprised 835 subjects from 12 short-term 
trials involving either exclusive evaluation of subjects with hyponatremia 
(9 trials) or substantial subpopulations of subjects with hyponatremia (3 
CHF trials). The 511 subjects in the hyponatremia trials were exposed to 
oral tolvaptan doses ranging from 5 to 60 mg, for a total of 8339 days of 
exposure.  In the 9 hyponatremia trials, the most commonly reported 
TEAEs (> 5% incidence) in the tolvaptan subjects were thirst, dry mouth, 
peripheral oedema, nausea, dizziness, fatigue, constipation, headache, 
ascites, diarrhoea, pollakiuria, asthenia, hypotension, pyrexia, and 
hypokalaemia.  The most commonly reported TEAEs (> 5% incidence) in 
the placebo subjects were peripheral oedema, diarrhoea, headache, ascites, 
vomiting, dyspnoea, nausea, and hypotension.  The IB provides a review 
of the adverse events (AEs) experienced with tolvaptan during clinical 
trials.
2.1.1 Core 
Safety Follow-
up Component:
The primary purpose of this component of this trial is to 
follow children and adolescent subjects who have 
previously participated in a trial of titrated oral IMP 
(tolvaptan in Trial 156-08-276; tolvaptan or placebo in Trial 
156-13-207 or Trial 156-12-205) for dilutional (euvolemic 
or hypervolemic) hyponatremia regardless of their 
The primary purpose of this component of this trial is to follow children 
and adolescent subjects who have previously participated in a trial of 
titrated oral IMP (tolvaptan in Trial 156-08-276; tolvaptan or placebo in 
Trial 156-13-207 or Trial 156-12-205) for dilutional (euvolemic or 
hypervolemic) hyponatremia for safety, regardless of their treatment status 


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treatment status with tolvaptan.  The minimum duration of 
safety follow-up will be 6 months.
with tolvaptan.  The duration of safety follow-up will be 6 months.
2.1.2 Optional 
Tolvaptan 
Treatment 
Component:
Children and adolescent subjects who have previously 
participated in a tolvaptan hyponatremia trial (Trials 156-
08-276, 156-13-207, or 156-12-205) who meet the 
eligibility criteria for treatment with tolvaptan may be 
eligible for one or more additional cycles of tolvaptan 
treatment.  
Depending upon clinical need and the investigator’s 
discretion, subjects in the core safety follow-up component 
may receive no treatment, be treated per the local standard 
of care for hyponatremia, or start treatment with tolvaptan.  
Based on the various underlying etiologies contributing to 
hyponatremia, the need for treatment may differ per 
individual subject.  Therefore, some of the subjects may 
require a regimen with tolvaptan to supplement treatment 
following the completion of the earlier short-term efficacy, 
safety, PK, and PD trials (Trials 156-08-276, 156-13-207, 
or 156-12-205), and this protocol is designed to 
accommodate short-term, long-term, and repeated tolvaptan 
treatment cycles as necessary.  Each tolvaptan treatment 
cycle will consist of a titration phase and a maintenance 
phase, with a planned discontinuation of treatment on Day 
30 for assessment of the need for continued treatment.  
After demonstrating the need for continued tolvaptan 
treatment beyond the first 30 days, subjects taking 
concomitant medications, with underlying conditions, or 
receiving treatments that contraindicate the discontinuation 
Any subject enrolled in the core safety follow-up component who has a 
medical need for tolvaptan and who meets the eligibility criteria for 
treatment with tolvaptan may be eligible for one or more additional cycles 
of tolvaptan treatment.  
Depending upon clinical need and the investigator’s discretion, subjects in 
the core safety follow-up component may receive no treatment, be treated 
per the local standard of care for hyponatremia, or start treatment with 
tolvaptan.  Based on the various underlying etiologies contributing to 
hyponatremia, the need for treatment may differ per individual subject.  
Therefore, some of the subjects may require a regimen with tolvaptan to 
supplement treatment following the completion of the earlier short-term 
efficacy, safety, PK, and PD trials (Trials 156-08-276, 156-13-207, or 
156-12-205), and this protocol is designed to accommodate short-term, 
long-term, and repeated tolvaptan treatment cycles as necessary.  
Each tolvaptan treatment cycle will consist of a titration phase and a 
maintenance phase. Each treatment cycle will have a planned interruption 
of treatment on Day 30 for assessment of the need for continued treatment. 
Subjects who are expected to receive tolvaptan for greater than 30 days 
consecutive duration should demonstrate the need for continued treatment 
by discontinuing tolvaptan for up to 2 consecutive doses while undergoing 
close monitoring of serum sodium levels.  However, there is a subgroup 
ofsubjects who have an identifiable cause for hyponatremia that has not 
(or cannot be) changed that will be excused from this brief interruption of 
tolvaptan.  Examples of such causes include concomitant treatment for 
refractory seizures with a hyponatremia-inducing medication such as 


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of tolvaptan treatment may be exempted from treatment 
discontinuation.  
oxcarbazepine (which can increase vasopressin production by the 
pituitary) that cannot be changed or discontinued, or subjects with a 
known underlying hyponatremia inducing condition such as volume 
overload from a failing Fontan repair.
It is recognized that the pediatric population is a vulnerable subgroup and 
there are risks in conducting a clinical trial in the pediatric population.  
However, given the possible serious and life-threatening consequences of 
untreated hyponatremia, it is necessary to study hyponatremia treatment in 
children.  Children have different physiology and metabolisms from adults 
and, therefore, it is not sufficient to study hyponatremia treatment in the 
adult population to determine the proper course of treatment for 
hyponatremia in the pediatric population.  A clear understanding of 
exposure-response in adults that can be applied to pediatrics (or from one 
pediatric group to another) has not yet been established, furthering the 
need for this trial.  
Every effort will be made to anticipate and reduce known risks.  This trial 
was designed to minimize the number of participants and the number of 
procedures, consistent with good study design.  Children will be 
continuously monitored for signs of distress during this trial.  The risk 
threshold for subjects will be constantly monitored by the investigator.  A 
detailed list and description of the safety monitoring to be conducted 
during this trial can be found in Section 3.7.4..
2.2 Dosing 
Rationale:
In the optional tolvaptan treatment component of the trial, 
eligible subjects with a demonstrated clinical need will be 
dosed with tolvaptan based on age, weight, and the use of 
CYP3A4 inhibitors.  Subjects < 2 years of age, or < 10 kg, 
or those who cannot swallow a tablet, will be excluded until 
In the optional tolvaptan treatment component of the trial, eligible subjects 
with a demonstrated clinical need will be dosed with tolvaptan based on 
age, weight, and the use of CYP3A4 inhibitors.  Subjects < 2 years of age, 
or < 10 kg, or those who cannot swallow a tablet, will be excluded from 
the treatment option of this protocol until an alternate formulation 


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an oral liquid formulation becomes available.  Subjects 
2 years of age and weighing 10 to < 20 kg will receive 
an oral QD dose of tolvaptan starting as a 3.75-mg spray-
dried tablet.  Subjects weighing 20 to 50 kg, inclusive, will 
receive an oral QD dose of tolvaptan starting as a 7.5-mg 
spray-dried tablet.  Subjects weighing > 50 kg will receive 
an oral QD dose of tolvaptan starting as a 15-mg spray-
dried tablet.  For subjects weighing 20 kg and taking 
moderate inhibitors of CYP3A4, a half-dose will be used 
(3.75 or 7.5 mg, by weight).  For subjects weighing > 50 kg 
and taking potent inhibitors of CYP3A4, a one-quarter dose 
will be used (3.75 mg).  Subjects weighing < 20 kg and who 
are taking any CYP3A4 inhibitors will be excluded from 
the trial until such time that an oral liquid formulation is 
available.
becomes available.  The liquid suspension formulation available for short-
term use in the 156-08-276 trial is not available in this trial.  Subjects 
2 years of age and weighing 10 to < 20 kg will receive an oral QD 
dose of tolvaptan starting as a 3.75-mg spray-dried tablet.  Subjects 
weighing 20 to 50 kg, inclusive, will receive an oral QD dose of tolvaptan 
starting as a 7.5-mg spray-dried tablet.  Subjects weighing > 50 kg will 
receive an oral QD dose of tolvaptan starting as a 15-mg spray-dried 
tablet.  For subjects weighing 20 kg and taking moderate inhibitors of 
CYP3A4, a half-dose will be used (3.75 or 7.5 mg, by weight).  For 
subjects weighing > 50 kg and taking potent inhibitors of CYP3A4, a 
one-quarter dose will be used (3.75 mg).  Subjects weighing < 20 kg and 
who are taking any CYP3A4 inhibitors will be excluded from the optional 
tolvaptan treatment until such time that an alternate formulation is 
available.
Figure 3.1-1 
Trial Design 
Schematic:
Schematic revised to reflect updated text in this section.
3.1.1.1 Core 
Safety Follow-
up Component 
Phases:
Subjects enrolled in this trial are required to complete 7 
visits regardless of their treatment status with tolvaptan.  
The Baseline Visit as well as Month 2, 4 and 6 Visits are 
performed in clinic while Month 1, 3 and 5 Visits can be 
conducted via telephone.  During the in clinic visits subjects 
are evaluated for relevant information.
Since all pediatric subjects (children and adolescents) who 
previously participated in a trial of titrated IMP (tolvaptan 
in Trial 156-08-276; tolvaptan or placebo in 
Trial 156-13-207 or 156-12-205) are eligible to participate 
Subjects enrolled in this trial are required to complete 7 visits regardless 
of their treatment status with tolvaptan as well as the follow-up telephone 
calls until the trial is closed.  The Baseline Visit as well as Month 2, 4 and 
6 Visits are performed in clinic while Month 1, 3 and 5 Visits can be 
conducted via telephone.  During the in clinic visits subjects are evaluated 
for relevant trial information.  After completion of the 6 month core 
follow-up visits, subjects will continue to be contacted at 3 month 
intervals to obtain basic safety updates.
All pediatric subjects (children and adolescents) who previously 
participated in a trial of titrated IMP (tolvaptan in Trial 156-08-276; 


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in this trial there is no screening phase.  Similarly, since the 
goal of the trial is to collect follow-up information for prior 
treatment there is no separate follow-up phase.
tolvaptan or placebo in Trial 156-13-207 or 156-12-205) are eligible to 
participate in this trial.  There is no screening phase.
3.1.2 Optional 
Tolvaptan 
Treatment 
Component:
Subjects enrolled in the 6-month core safety follow-up 
component may meet the criteria for treatment with 
tolvaptan.  This subset of the study population may receive 
cycles of tolvaptan per clinical need to treat their 
hyponatremia.  If a subject has a clinical need for treatment 
with tolvaptan, the subject may be screened for eligibility to 
be dosed within this trial.  The subject must have been off 
treatment with the IMP for 7 days following the end of 
treatment in the previous trial of titrated oral IMP 
(tolvaptan in Trial 156-08-276, tolvaptan or placebo in 
Trials 156-13-207 and 156-12-205) to assess the subject’s 
clinical need for dosing.  Eligibility for tolvaptan treatment 
must be determined between Day -4 and Day -1 of each 
dosing cycle.  Subjects can be treated with tolvaptan during 
and/or after the 6-month core safety follow-up component 
after evaluating the subject using the criteria outlined in 
Appendix 5.
Thirty days after the start of tolvaptan treatment, all 
subjects receiving tolvaptan will discontinue treatment for 
up to 72 hours, during which the need for continuing 
treatment with tolvaptan will be reassessed.  Subjects who 
resume dosing can do so at the same dose or a lower dose 
without having to go through the full titration cycle again. 
Subjects who have a dosing discontinuation of > 72 hours 
must repeat the full titration cycle in a hospital setting.The 
Subjects enrolled in the 6-month core safety follow-up component who 
have a clinical need for tolvaptan, per the investigator’s assessment, and 
meet the criteria for treatment with tolvaptan, may receive cycles of 
tolvaptan to treat their hyponatremia. The subject must have completed 
the follow-up period of the previous trial prior to receiving the first dose 
of IMP. Eligibility for tolvaptan treatment must be determined between 
Day -4 and Day -1 of each dosing cycle.  Subjects can be treated with 
tolvaptan during and/or after the 6-month core safety follow-up 
component after evaluating the subject using the criteria outlined in 
Appendix 5.
Thirty days after the start of tolvaptan treatment in the first cycle, subjects 
receiving tolvaptan will interrupt treatment for 2 doses (Days 31-32).  The 
need for continuing treatment will be assessed minimally once daily 
during this time.  Subjects who resume dosing within 72 hours post last 
dose (either on Day 32 or by the morning of Day 33), based on medical 
need, can do so at the same dose or a lower dose without having to go 
through the full titration cycle again.  Subjects who have a dosing 
discontinuation of > 2 doses must enter a new treatment cycle and repeat 
the full titration cycle in a hospital setting.
Pediatric subjects in 156-11-294 who interrupt tolvaptan treatment (for 2 
doses) for the purpose of re-evaluation to continue treatment beyond 30 
days will have serum sodium levels and neurocognitive symptoms 
monitored closely.  Subjects who demonstrate a decline in serum sodium 
level will be restarted at the prior dose of tolvaptan as per clinician 


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optional tolvaptan treatment component of the trial does not 
have a fixed stopping point.  Subjects who have an ongoing 
need for treatment can continue to receive tolvaptan per the 
investigator’s clinical judgment until they no longer have a 
need for treatment or all subjects have completed the 6 
month Core Follow-up Component of the trial.  Subjects 
who terminate tolvaptan treatment will have follow-up 
visits at 24 hours (4 hours), and at 7 (1) days post-last 
dose, and a telephone call at 14 days (+ 2 days) post-last 
dose.  Additional follow-up contacts will be performed on a 
regular basis until the end of the trial.
judgment. Subjects whose serum sodium declines ≥ 4 mEq/L (mmol/L) or 
who exhibit symptoms of hyponatremia will be immediately placed under 
direct observation (e.g., short stay unit) as per clinician judgment and will 
be restarted at either a lower dose or the previous dose of tolvaptan and 
closely monitored until stable.
Investigators should consider the overall clinical status of the subject 
(including underlying etiology of hyponatremia and volume assessment), 
prior response to tolvaptan, concomitant medications, age, and weight 
when determining the appropriate dose at which to restart a subject after a 
brief discontinuation of tolvaptan to assess the need for further treatment.  
Investigators should discuss any concerns with the medical monitor.  
The optional tolvaptan treatment component of the trial does not have a 
fixed stopping point.  Subjects who have an ongoing need for treatment 
can continue to receive tolvaptan per the investigator’s clinical judgment 
until they no longer have a need for treatment or all subjects have 
completed the 6 month Core Follow-up Component of the trial.  Subjects 
who terminate tolvaptan treatment will have follow-up visits at 24 hours 
(4 hours), and at 7 (1) days post-last dose, and a telephone call at 14 
days (+ 2 days) post-last dose.  Additional follow-up contacts will be 
performed on a regular basis until the end of the trial.
3.1.2.1.2 
Treatment 
Initiation and 
Maintenance:
During the first 30 days of treatment subjects should have 
serum sodium assessments at a minimum of once daily 
during the Titration Phase on Day 1 up to Day 4 of 
treatment, and at a minimum of once weekly thereafter once 
on a stable dose (ie, on Days 7, 14, 21, and 28). 
After the first 30 consecutive days of treatment, all subjects 
who receive tolvaptan will be assessed for the need to 
During the first 30 days of treatment subjects should have serum sodium 
assessments at a minimum of once daily during the Titration Phase on Day 
1 up to Day 4 of treatment, and at a minimum of once weekly thereafter 
once on a stable dose (ie, on Days 7, 14, 21, and 28). 
In addition to serum sodium samples obtained for treatment qualification 
and efficacy endpoints, supplemental samples for the purposes of safety 
assessment only can be obtained using a point of care sodium assessment 


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continue treatment (Section 3.7.3.2.4).  However, subjects 
may be assessed, per investigator’s discretion, for the need 
for ongoing treatment with tolvaptan at any time point 
during treatment.  Subjects who demonstrate a need for 
tolvaptan treatment may continue treatment to maintain the 
normal or clinician-directed target range serum sodium. 
Procedures for reinitiation of tolvaptan treatment for 
subjects with a clinical need per the investigator’s 
assessment are described in Section Error! Reference 
source not found..
Tolvaptan treatment can be discontinued and reinitiated as 
needed per individual subject’s need (eg, during 
chemotherapy treatments).  If subjects are off tolvaptan 
treatment for > 72 hours, reinitiation of treatment will 
require reassessment of eligibility criteria and will begin in 
a hospital setting.  Tolvaptan should be titrated with regular 
serum sodium assessments (Section 3.2.1.2 and 
Section 3.7.4.1).  
unit, where available, on Day 1 at 4 to 6 hours postdose and at 18 hours 
postdose.  This sodium safety assessment will be repeated at 6 and 18 
hours postdose each day for the remainder of titration.  A point of care 
assessment unit is preferred; however, regular blood draws may be used 
(especially if they can be combined with standard of care labs).
After the first 30 consecutive days of treatment, all subjects who receive 
tolvaptan will have a scheduled interruption of tolvaptan to assess the need 
to continue treatment (Section 3.7.3.2.4).  However, subjects may be 
assessed, per investigator’s discretion, for the need for ongoing treatment 
with tolvaptan at any time point during treatment.  Subjects who 
demonstrate a need for tolvaptan treatment may continue treatment to 
maintain the normal or clinician-directed target range serum sodium.  
Procedures for reinitiation of tolvaptan treatment for subjects with a 
clinical need per the investigator’s assessment are described in 
Section Error! Reference source not found..
Tolvaptan treatment can be discontinued and reinitiated as needed per 
individual subject’s need (eg, during chemotherapy treatments).  If 
subjects are off tolvaptan treatment for > 72 hours, reinitiation of 
treatment will require reassessment of eligibility criteria and will begin in 
a hospital setting as part of a new treatment cycle.  Tolvaptan should be 
titrated with regular serum sodium assessments (Section 3.2.1.2 and 
Section 3.7.4.1).
3.1.2.1.3 Follow-
up Phase (End 
of Tolvaptan 
Treatment 
Cycle):
Subjects who discontinue tolvaptan treatment in the 
optional tolvaptan treatment component per the 
investigator’s decision will return to the clinical trial site for 
serum sodium assessments at 24 (4) hours and at 7 (1) 
days post-last dose, and will receive follow-up telephone 
Subjects who discontinue tolvaptan treatment in the optional tolvaptan 
treatment component per the investigator’s decision will return to the 
clinical trial site for serum sodium assessments at 24 (4) hours and at 7 
(1) days post-last dose, and will receive follow-up telephone calls at 14 
(+2) days and every 3 months (2 weeks) post-last dose. In the Follow-


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calls at 14 (+2) days and every 3 months (2 weeks) post-
last dose. In the Follow-up Phase (ie, at the end of Month 6 
or at the end of the tolvaptan treatment), subjects should 
have serum sodium assessments at 24 (4) hours and 
7 (+ 1) days, and 14 (+2) days post-last dose.  ALT, AST, 
and BT should be assessed at 24 (4 hours) post-last dose, 
if more than 1 month has elapsed since LFTs were 
performed.  An IRE form will be completed if the subject is 
a potential Hy’s Law case (see Section 5.4).  Potential Hy’s 
Law cases will be followed up until the ALT, AST, and BT 
values are within normal limits.
up Phase (ie, at the end of Month 6 or at the end of the tolvaptan 
treatment), subjects should have serum sodium assessments at 24 (4) 
hours and 7 (+ 1) days post-last dose.  ALT, AST, and BT should be 
assessed at 24 (4 hours) post-last dose, if more than 1 month has elapsed 
since LFTs were performed.  An IRE form will be completed if the subject 
is a potential Hy’s Law case (see Section 5.4).  Potential Hy’s Law cases 
will be followed up until the ALT, AST, and BT values are within normal 
limits.
3.2 Treatments:
For all subjects enrolled in the core safety follow-up 
component of the trial, the need for initiation of tolvaptan 
treatment will be assessed per protocol serum sodium 
guidelines and the duration of tolvaptan administration will 
determined by the PI per the subject’s medical need. 
For all subjects enrolled in the core safety follow-up component of the 
trial, the need for initiation of tolvaptan treatment will be assessed per the 
protocol’s serum sodium guidelines and the duration of tolvaptan 
administration will be determined by the PI per the subject’s medical 
need. 
3.2.1.2 Titration 
Guidelines for 
the Optional 
Tolvaptan 
Treatment 
Component:
Subjects will be administered tolvaptan on an age- and 
weight-based scale.  Tolvaptan doses can be titrated QD 
and will be based on serum sodium levels assessed at 
> 20 hours following initiation of therapy and each 
subsequent dose; titration may not occur within 20 hours of 
the previous dose.  Titration is limited to no more than 
twice the previous dose and will be limited to the maximum 
dose per body weight.  A change in serum sodium 
4 mEq/L (mmol/L) from baseline should warrant titration.

Subjects < 2 years of age or weighing < 10 kg are 
Subjects will be administered tolvaptan on an age- and weight-based scale.  
Tolvaptan doses can be titrated QD and will be based on serum sodium 
levels assessed at > 20 hours following initiation of therapy and each 
subsequent dose; titration may not occur within 20 hours of the previous 
dose.  Titration is limited to no more than twice the previous dose and will 
be limited to the maximum dose per body weight.  A change in serum 
sodium 4 mEq/L (mmol/L) from baseline should warrant titration.

Subjects < 2 years of age or weighing < 10 kg are not eligible for 
treatment until an alternate formulation is available.  

Subjects 2 years of age and weighing 10 to < 20 kg will be 


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excluded until an oral liquid formulation is 
available.  

Subjects 2 years of age and weighing 10 to < 
20 kg will be given a 3.75-mg tablet on Day 1 with 
possible up-titration to 7.5- and 15-mg tablet 
doses.

Subjects weighing 20 to 50 kg, inclusive, will be 
given a 7.5-mg tablet on Day 1 with possible up-
titration to 15- and 30-mg tablet doses.

Subjects weighing > 50 kg will be given a 15-mg 
tablet on Day 1 with possible up-titration to 30-
and 60-mg tablet doses. 

Subjects weighing 20 kg and taking moderate 
inhibitors of CYP3A4 will be given a half-dose 
(3.75 or 7.5 mg, by weight).  

Subjects weighing > 50 kg and taking potent 
inhibitors of CYP3A4 will be given a one-quarter 
dose.

Subjects weighing < 20 kg and who are taking any 
CYP3A4 inhibitors will be excluded until such 
time that an oral liquid formulation is available.
given a 3.75-mg tablet on Day 1 with possible up-titration to 7.5-
and 15-mg tablet doses.

Subjects weighing 20 to 50 kg, inclusive, will be given a 7.5-mg 
tablet on Day 1 with possible up-titration to 15- and 30-mg tablet 
doses.

Subjects weighing > 50 kg will be given a 15-mg tablet on Day 1 
with possible up-titration to 30- and 60-mg tablet doses. 

Subjects weighing 20 kg and taking moderate inhibitors of 
CYP3A4 will be given a half-dose (3.75 or 7.5 mg, by weight).  

Subjects weighing > 50 kg and taking potent inhibitors of 
CYP3A4 will be given a one-quarter dose.

Subjects weighing < 20 kg and who are taking any CYP3A4 
inhibitors will be excluded until such time that an alternate 
formulation is available.
3.2.2 Duration 
of Optional 
Tolvaptan 
Treatment:
For subjects who require long-term treatment, each subject 
will be required to temporarily discontinue treatment at 30 
days after the start of tolvaptan and be evaluated for 
continued need for tolvaptan treatment.  
For subjects who require long-term treatment, each subject (exceptions 
listed in Section 2.1.2) will be required to temporarily discontinue 
treatment at 30 days after the start of tolvaptan and be evaluated for 
continued need for tolvaptan treatment.  
3.2.3 Rescue 
Therapy:
A subject requiring rescue therapy at any time during the 
optional tolvaptan treatment component will be 
discontinued from tolvaptan prior to receiving rescue 
therapy and should continue to be followed per the schedule 
of assessments in the core safety follow-up component of 
the trial.  Treatment may be reinitiated only per consultation 
A subject requiring rescue therapy at any time during the optional 
tolvaptan treatment component will be discontinued from tolvaptan prior 
to receiving rescue therapy and should continue to be followed per the 
schedule of assessments in the optional tolvaptan treatment component 
and the core safety follow-up component of the trial, as appropriate.  
Treatment may be reinitiated only per consultation with the medical 


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with the medical monitor.  Subjects who have received 
rescue therapy because of inadequate response to tolvaptan 
will not be allowed to reinitiate tolvaptan treatment. 
monitor.  Subjects who have received rescue therapy because of 
inadequate response to tolvaptan will not be allowed to reinitiate tolvaptan 
treatment. 
3.3.1 Core 
Safety Follow-
up Component:
Up to 140 male or female subjects may be eligible for this 
trial.  All subjects will have participated in one of the 
previous tolvaptan pediatric hyponatremia trials (156-08-
276, 156-13-207, or 156-12-205).  All subjects will be 
observed for post-treatment safety for at least 6 months.  
Subjects enrolled in the core safety follow-up component 
may enter the optional tolvaptan treatment component of 
the trial at any time during the conduct of the trial based on 
clinical need and the investigator’s discretion.
Approximately 140 male or female subjects may be eligible for this trial.  
All subjects will have participated in one of the previous tolvaptan 
pediatric hyponatremia trials (156-08-276, 156-13-207, or 156-12-205).  
All subjects will be observed for safety for 6 months regardless of 
treatment status and followed until the end of the trial.  Subjects enrolled 
in the core safety follow-up component may enter the optional tolvaptan 
treatment component of the trial at any time during the conduct of the trial 
based on clinical need and the investigator’s discretion.
3.3.2 Optional 
Tolvaptan 
Treatment 
Component:
Subjects enrolled in the Core Safety Follow-up Component 
of the trial may be eligible for treatment with tolvaptan.  
These subjects include, but are not limited to, those 
diagnosed and admitted to a hospital for treatment of heart 
failure, hepatocellular disease (including cirrhosis), or 
SIADH/other.  Subjects with acute hyponatremia or 
hyponatremia expected to resolve spontaneously will be 
ineligible for tolvaptan treatment.  Children with an 
impaired ability to sense or communicate their thirst will 
either be required per protocol to undergo closer in hospital 
observation, laboratory and urine output monitoring, or will 
be ineligible for tolvaptan treatment if this is not possible.  
Children with hypovolemic hyponatremia or those who are 
at risk of such, secondary to any underlying conditions that 
Subjects enrolled in the Core Safety Follow-up Component of the trial 
may be eligible for treatment with tolvaptan.  These subjects include, but 
are not limited to, those diagnosed and admitted to a hospital for treatment 
of heart failure, hepatocellular disease (including cirrhosis), or 
SIADH/other.  Subjects with acute hyponatremia or hyponatremia 
expected to resolve spontaneously will be ineligible for tolvaptan 
treatment.  Children with an impaired ability to sense or communicate 
their thirst will either be required to undergo closer observation, laboratory 
and urine output monitoring, or will be ineligible for tolvaptan treatment if 
this is not possible.  Children with hypovolemic hyponatremia or those 
who are at risk of such, secondary to any underlying conditions that cause 
volume depletion, are ineligible for tolvaptan treatment.
For initiation or reinitiation of tolvaptan treatment in the Optional 


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cause volume depletion, are ineligible for tolvaptan
treatment.
Tolvaptan Treatment Component of the trial additional criteria apply as 
outlined in Appendix 5.
3.4.1 Informed 
Consent/Assent:
Written informed consent or patient information sheet (PIS) 
and assent as appropriate will be obtained from the 
subject’s parent or legal guardian, in accordance with 
requirements of the trial center’s institutional review 
board/independent ethics committee (IRB/IEC).  The 
subject, as required by the trial center’s IRB/IEC, must 
provide informed assent at baseline (which may be the final 
visit in the previous titrated oral IMP trial) and as such must 
be able to understand that he or she can withdraw from the 
trial at any time.  Age appropriate assent documents will be 
created and subjects who are able will be required to 
reconsent or assent as appropriate if they matriculate from 
one age group to another.  Subjects who became legal 
adults during the previous trial of titrated oral IMP 
(tolvaptan in Trial 156-08-276, tolvaptan or placebo in 
Trials 156-13-207 and 156-12-205) or who become legal 
adults during this trial will be required to provide written 
informed consent as soon as they reach legal age.
Consent and assent will be documented on a written 
informed consent form (ICF).  The ICF will be approved by 
the same IRB/IEC that approves this protocol. Each ICF 
will comply with the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) 
Written informed consent and assent as appropriate will be freely obtained 
from the subject’s parent or legal guardian, as applicable for local laws, in 
accordance with requirements of the trial center’s institutional review 
board/independent ethics committee (IRB/IEC).  The subject, as required 
by the trial center’s IRB/IEC, must provide informed assent at baseline 
(which may be the final visit in the previous titrated oral IMP trial) and as 
such must be able to understand that he or she can withdraw from the trial 
at any time.  Age appropriate assent documents will be created and 
subjects who are able will be required to reconsent or assent as appropriate 
if they matriculate from one age group to another.  Subjects who became 
legal adults during the previous trial of titrated oral IMP (tolvaptan in 
Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 156-12-
205) or who become legal adults during this trial will be required to 
provide written informed consent as soon as they reach legal age.
Consent and assent will be documented on a written informed consent 
form (ICF).  The ICF will be approved by the same IRB/IEC that approves 
this protocol.  Each ICF will comply with the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) Guideline and local 
regulatory requirements.  The investigator agrees to obtain approval from 
the sponsor of any written ICF used in the trial, prior to submission to the 
IRB/IEC.
Investigators may discuss trial availability and the possibility for entry 


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Guideline and local regulatory requirements.  The 
investigator agrees to obtain approval from the sponsor of 
any written ICF used in the trial, prior to submission to the 
IRB/IEC.
Investigators may discuss trial availability and the 
possibility for entry with a potential subject and his/her 
family without first obtaining consent and assent, as 
applicable.  However, informed consent/assent (as 
applicable) must be obtained and documented prior to 
initiation of any procedures that are performed solely for 
the purpose of determining eligibility for this trial, 
including withdrawal from current medication(s).
with a potential subject and his/her family without first obtaining consent 
and assent, as applicable.  However, informed consent/assent (as 
applicable) must be obtained and documented prior to initiation of any 
procedures that are performed solely for the purpose of determining 
eligibility for this trial, including withdrawal from current medication(s).  
Investigators may obtain consent and assent for this trial while the subject 
is still enrolled in the previous trial (Trial 156-08-276, Trial 156-13-207 
and Trial 156-12-205). 
...Subjects’ parents or legal guardian(s) may be asked to sign additional 
ICFs if the protocol is amended to significantly add or change procedures.  
Subjects who are able may be asked to re-assent as appropriate if the 
protocol is amended to significantly add or change procedures.
3.4.3 Exclusion 
Criteria:
There are no exclusion criteria for entry into the safety 
follow-up component of this trial.
For initiation or reinitiation of tolvaptan treatment in the 
Optional Tolvaptan Treatment Component of the trial 
additional criteria apply as outlined in Appendix 5.
There are no exclusion criteria for entry into the trial.
3.5.2.2 Safety 
Variables:
The primary safety variables are the following:

AE reporting

Growth percentiles for body height and body 
weight

Tanner Staging

Change from baseline in serum sodium 
concentration
The safety variables are the following:

AE reporting

Growth percentiles for body height and body weight

Tanner Staging

Change from baseline in serum sodium concentration
3.5.2.3 
Pharmacokineti
The PK endpoints are the plasma concentrations of 
tolvaptan and metabolites in subjects who have continued 
The PK endpoints are the plasma concentrations of tolvaptan and 
metabolites in subjects who have continued tolvaptan therapy for 


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c Variable: 
Optional 
Tolvaptan 
Treatment 
Component
tolvaptan therapy for 8 consecutive weeks, ignoring short 
interruptions to assess need for continued therapy.
8 consecutive weeks, ignoring short interruptions (up to 2 missed doses) to 
assess need for continued therapy.


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Old Text:  Table 3.7.1-1
Schedule of Assessments
Table 3.7.1-1 Core Safety Follow-up Component:  Schedule of Assessments for All Subjects
Procedures
Baselinea
Month 1
(+2 Weeks)
Month 2
(+2 Weeks)
Month 3
(+2 Weeks)
Month 4
(+2 Weeks)
Month 5
(+2 Weeks)
Month 6 or Early 
Termination
(+2 Weeks)
Informed consent and assent
X
Review inclusion criteria
X
Demographic information
X
Telephone assessmentb
X
X
X
In-clinic assessment
X
X
X
X
Medical and hyponatremia history
X
X
X
X
Vital signsc
X
X
X
X
Directed physical examination
X
X
X
X
Body height/weight/ growth percentiles
X
X
X
X
Tanner Staging
X
X
X
X
Serum sodium 
X
X
X
X
Assess ALT, AST, and BT
X
X
X
X
Neurocognitive Assessmentd
X
X
X
X
Quality of Life
X
X
X
X
Concomitant medications
Adverse events
aThe final laboratory assessments from the previous trial  (tolvaptan in Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 156-12-205) can serve 
as the baseline laboratory assessments for this trial.  All assessments, with the exception of the neurocognitive assessment, can be carried over from 
previous trial of titrated oral IMP to this trial, if possible.  Body height, body weight, Tanner Staging, and baseline laboratory assessments can be carried 
forward from the last visit in the previous trial if done within one month, but all other assessments must be completed at the baseline visit and all including 
height, Tanner Staging and laboratory assessments must be re-done if more than one month passes between trials.
bTelephone calls can be replaced with clinical site visits.
cVital signs to be assessed include supine blood pressure, heart rate, respiratory rate, and temperature.  Vital signs should be assessed prior to any blood 
draws.
dNeurocognitive assessment will be performed at baseline and at Months 2, 4, and 6, and should be done within 1 hour of blood draws for serum sodium 
assessment. 


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New Text:  Table 3.7.1-1
Schedule of Assessments
Table 3.7.1-1 Core Safety Follow-up Component:  Schedule of Assessments for All Subjects
Procedures
Baselinea
Month 1
(+2 
Weeks)
Month 2
(+2 
Weeks)
Month 3
(+2 
Weeks)
Month 4
(+2 
Weeks)
Month 5
(+2 
Weeks)
Month 6 or 
Early 
Termination
(+2 Weeks)
every 3 
months 
(2 weeks)
Informed consent and assent
X
Review inclusion criteria
X
Demographic information
X
Telephone assessmentb
X
X
X
X
In-clinic assessment
X
X
X
X
Medical history
X
Hyponatremia history
X
X
X
X
Vital signsc
X
X
X
X
Directed physical examination
X
X
X
X
Body height/weight/ growth percentiles
X
X
X
X
Tanner Stagingd
X
X
Serum sodium
X
X
X
X
Assess ALT, AST, and BT
X
X
X
X
Neurocognitive Assessmente
X
X
X
X
Quality of Life
X
X
X
X
Concomitant medications
Adverse events
a The final laboratory assessments for LFT from the previous trial  (tolvaptan in Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 156-12-205)
can serve as the baseline laboratory assessments for this trial.  Assessments, with the exception of the serum sodium, QoL, and neurocognitive assessment, 
can be carried over from a previous trial of titrated oral IMP to this trial, if possible and if not more than 1 month has passed between the 2 trials.
bTelephone calls can be replaced with clinical site visits.
cVital signs to be assessed include supine blood pressure, heart rate, respiratory rate, and temperature.  Vital signs should be assessed prior to any blood 
draws.
dA subject who reaches Stage 5 (both in pubic hair and genitalia) does not need to continue with Tanner Staging.


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eNeurocognitive assessment will be performed at baseline and at Months 2, 4, and 6, and should be done within 1 hour of blood draws for serum sodium 
assessment. 


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3.7.2 Optional 
Tolvaptan 
Treatment 
Component:
Trial treatment will begin and be titrated in a hospital 
setting.  
Trial treatment will begin and titration must occur in a hospital setting.  
... If subjects are off tolvaptan treatment for > 72 hours, reinitiation of 
treatment, starting with titration, will require reassessment of the 
eligibility criteria, and titration will begin in a hospital setting as part of a 
new treatment cycle.


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Old Text:  Table 3.7.2-1
Schedule of Assessments
Table 3.7.2-1 Schedule of Assessments for Each Treatment Cycle
Proceduresa
Pretreat
ment
Baselineb
Titration Phaseb
Post-titration
Treatment 
Cycle 
Month 2
Treatment Cycle 
Month 3+
(Maintenance)
Follow- up Phase
Days 
-4 to -1
Day 
1
Day 
2 
and 
3
Day 
4
Day 
7, 14 
and 
21
Day 
30 
(1)
Day 
33 
(-1)
every 2 
weeks 
(2 days)
Once monthly 
(2 days)
24 (4) 
hours 
post-last 
dose
7 (1) 
days 
post-last 
dose
14 (2) 
days 
post-last 
dose
every 3 
months 
(2 
weeks)
Review 
eligibility 
criteria for 
treatment
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Directed 
physical exam
X
X
Body height and 
weight/
growth 
percentiles
X
X
Pregnancy testc
X
X
X
X
X
Clinical status 
assessment
X
X
X
X
Assess ALT, 
AST, and BTd
X
X
X
X
X
Assess serum 
sodiume
X
X
X
X
X
X
X
X
X
X
X
Tolvaptan 
dosingf
X
X
X
X
X
X
X
X


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Table 3.7.2-1 Schedule of Assessments for Each Treatment Cycle
Proceduresa
Pretreat
ment
Baselineb
Titration Phaseb
Post-titration
Treatment 
Cycle 
Month 2
Treatment Cycle 
Month 3+
(Maintenance)
Follow- up Phase
Days 
-4 to -1
Day 
1
Day 
2 
and 
3
Day 
4
Day 
7, 14 
and 
21
Day 
30 
(1)
Day 
33 
(-1)
every 2 
weeks 
(2 days)
Once monthly 
(2 days)
24 (4) 
hours 
post-last 
dose
7 (1) 
days 
post-last 
dose
14 (2) 
days 
post-last 
dose
every 3 
months 
(2 
weeks)
Confirm stable 
dose
X
Dispense 
tolvaptan drug 
kit
X
X
X
X
Assess need for 
continued 
treatment
X
Tolvaptan 
collection/
reconciliation
X
X
X
X
X
PK sample 
collectiong
X
X
Telephone call
X
X
Concomitant 
medications
Adverse events
aAssessments that are part of a Core Safety Follow-up Component Trial Visit which happens to overlap with a visit in the Optional Tolvaptan Treatment 
Component only need to be performed once.
bCycles can be repeated per clinical need.  If a subject is off tolvaptan treatment for > 72 hours, titration/reinitiation of tolvaptan will require reassessment of 
eligibility criteria and will begin in a hospital setting.


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cSerum or urine pregnancy tests will be performed on female subjects 12 years of age and female subjects < 12 years of age if menstruation has started.  In 
Treatment Cycle Month 2 a pregnancy test should be performed a month after the previous assessment.
dIn Treatment Cycle Month 2 liver function should be assessed a month after the previous assessment.
eSerum sodium will be assessed at the pretreatment baseline 48 hours prior to tolvaptan administration where 2 serum sodium assessments (<130 mEq/L 
[mmol/L) must be collected at least 12 hours apart.  On Day 1 a STAT serum sodium sample will be assessed at 2 to 4 hours prior to first dose and another 
sample at 8 hours post-dose.  On Day 2, 3 and 4 a sample will be assessed at 24 (4) hours post previous dose.  On Days 7, 14, 21, and 30 at 24 (4) hours 
post-previous dose.  At Day 33 serum sodium will be assessed between 48 and 72 hours post previous dose.  In Treatment Cycle Month 2 a sample will be 
assessed every 14 (2) days.  In Treatment Cycle Month 3 a sample will be assessed every month (2 days).
fThe dose will be titrated based on serum sodium results assessed at a minimum of 24-hour intervals (4 hours) from 3.75 to 7.5 to 15 mg for subjects 
2 years of age and weighing 10 to < 20 kg, from 7.5 to 15 to 30 mg for subjects weighing 20 to 50 kg, inclusive, or from 15 to 30 to 60 mg for subjects 
weighing > 50 kg.  Subjects may be sequentially titrated to the maximal dose allowed for their weight group.  After the first 30 days of treatment, subjects 
will discontinue treatment with tolvaptan for up to 72 hours (2 skipped doses) to assess continued need for treatment.
gOne PK sample should be taken after 8 weeks of continuous treatment per cycle.


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New Text:  Table 3.7.2-1
Schedule of Assessments
Table 3.7.2-1 Schedule of Assessments for Each Treatment Cycle
Proceduresa
Pretreat
ment
Baselineb
Titration Phaseb
Post-titration
Treatment 
Cycle 
Month 2
Treatment 
Cycle Month 
3+
(Maintenance)
Follow- up Phaseh
Days 
-4 to -1
Day 
1
Day 
2 
and 
3
Day 
4
Day 
7, 14 
and 
21
Day 
30 
(1)
Day 
31
(-1)
Day 
32
(-1)
Day 
33 
(-1)
Day 
34
(-1)
every 2 
weeks 
(2 days)
Once monthly 
(2 days)
24 
(4) 
hours 
post-
last 
dose
7 
(1) 
days 
post
-last 
dose
14 (2) 
days 
post-
last 
dose
Review 
eligibility 
criteria for 
treatment
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Directed 
physical exam
X
X
Body height and 
weight/
growth 
percentiles
X
X
Pregnancy testc
X
X
X
X
X
Clinical status 
assessment
X
X
X
X
X
X
X
Assess ALT, 
AST, and BTd
X
X
X
X
X
Assess serum 
sodiume
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tolvaptan 
dosingf
X
X
X
X
X
X
X
X
X


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Table 3.7.2-1 Schedule of Assessments for Each Treatment Cycle
Proceduresa
Pretreat
ment
Baselineb
Titration Phaseb
Post-titration
Treatment 
Cycle 
Month 2
Treatment 
Cycle Month 
3+
(Maintenance)
Follow- up Phaseh
Days 
-4 to -1
Day 
1
Day 
2 
and 
3
Day 
4
Day 
7, 14 
and 
21
Day 
30 
(1)
Day 
31
(-1)
Day 
32
(-1)
Day 
33 
(-1)
Day 
34
(-1)
every 2 
weeks 
(2 days)
Once monthly 
(2 days)
24 
(4) 
hours 
post-
last 
dose
7 
(1) 
days 
post
-last 
dose
14 (2) 
days 
post-
last 
dose
Confirm stable 
dose
X
Dispense 
tolvaptan drug 
kit
X
X
X
X
X
X
Assess need for 
continued 
treatment
X
Tolvaptan 
collection/
reconciliation
X
X
X
X
X
PK sample 
collectiong
X
X
Telephone call
X
Concomitant 
medications
Adverse events
aAssessments that are part of a Core Safety Follow-up Component Trial Visit which happens to overlap with a visit in the Optional Tolvaptan Treatment 
Component only need to be performed once.
bTitration can be up to 4 days.  Cycles can be repeated per clinical need.  If a subject is off tolvaptan treatment for > 72 hours, titration/reinitiation of tolvaptan 
will require reassessment of eligibility criteria and will begin in a hospital setting as part of a new treatment cycle.


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cPregnancy tests will be performed on female subjects 12 years of age and female subjects < 12 years of age if menstruation has started.  In Treatment Cycle 
Month 2 a pregnancy test should be performed a month after the previous assessment.
dIn Treatment Cycle Month 2 liver function should be assessed a month after the previous assessment.
eSerum sodium will be assessed at the pretreatment baseline 48 hours prior to tolvaptan administration where 2 serum sodium assessments (<130 mEq/L 
[mmol/L) must be collected at least 12 hours apart.  On Day 1 a STAT serum sodium sample will be assessed at 2 to 4 hours prior to first dose and another 
sample at 8 hours postdose.  On Day 2, 3 and 4 a sample will be assessed at 24 (4) hours post previous dose.  On Days 7, 14, 21, and 30 at 24 (4) hours 
post-previous dose.  At Day 33 serum sodium will be assessed between 48 and 72 hours post previous dose.  In Treatment Cycle Month 2 a sample will be 
assessed every 14 (2) days.  In Treatment Cycle Month 3 a sample will be assessed every month (2 days).  In addition to serum sodium samples 
obtained for treatment qualification and efficacy endpoints, supplemental samples for the purposes of safety assessment only can be obtained using a point 
of care sodium assessment unit, where available, on Day 1 at 4 to 6 hours postdose and at 18 hours postdose, as well as at 6 hours and 18 hours postdose 
each day for the remainder of titration.  A point of care assessment unit is preferred; however, regular blood draws may be used (especially if they can be 
combined with standard of care labs).
fThe dose will be titrated based on serum sodium results assessed at a minimum of 24-hour intervals (4 hours) from 3.75 to 7.5 to 15 mg for subjects 
2 years of age and weighing 10 to < 20 kg, from 7.5 to 15 to 30 mg for subjects weighing 20 to 50 kg, inclusive, or from 15 to 30 to 60 mg for subjects 
weighing > 50 kg.  Subjects may be sequentially titrated to the maximal dose allowed for their weight group.  After the first 30 days of treatment, subjects 
will discontinue treatment with tolvaptan for up to 72 hours (2 skipped doses) to assess continued need for treatment.
gOne PK sample should be taken after 8 weeks of continuous treatment per cycle.  This may include a discontinuation of < 72 hours to assess the subject’s 
need for continued treatment.
hSubjects who elect to opt out of treatment within a treatment cycle should immediately proceed to the Follow-up Phase.


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3.7.3.1.1 
Baseline for 
Core Safety 
Follow-up 
Component:
For all subjects who enroll in this trial, the final laboratory 
assessments in the previous trial can serve as the baseline 
laboratory assessments.   The following procedures will be 
performed during the baseline visit: 
1)
Trial procedures and information regarding the 
nature of the trial will be reviewed and written 
informed consent/assent will be obtained prior to 
any trial-related procedures.  Informed 
consent/assent needs to be obtained only before 
entering the trial for the first time.
h)
ICF, assent, and/or PIS will be obtained from 
each subject’s parent or legal guardian prior to 
any trial procedures being conducted.
i)
Each subject will indicate willingness to 
participate in the trial by signing or marking 
an assent form (as applicable) supplied for this 
purpose.
2)
Inclusion criteria will be reviewed.
8)
Body height and body weight will be transferred 
from the last assessments from the previous trial or 
measured, as appropriate. 
9)
Growth percentile will be calculated.  Prior growth 
development information should also be collected, 
if available.
10) Tanner Staging will be transferred from the last 
assessments from the previous trial or completed 
as part of the physical examination, as appropriate.  
Historical staging information should also be 
collected, if available.
11) The final laboratory assessments from the previous 
trial can serve as baseline laboratory assessments 
in this trial (see Appendix 6), as appropriate.
For all subjects who enroll in this trial, the final assessments in the 
previous trial can serve as the baseline assessments, as applicable.  If more 
than one month passes between the 2 trials, all assessments need to be 
completed.  The following procedures will be performed during the 
baseline visit: 
1)
Trial procedures and information regarding the nature of the trial 
will be reviewed and written informed consent/assent will be 
obtained prior to any trial-related procedures.  Investigators may 
obtain consent and assent for this trial while the subject is still 
enrolled in the previous trial (Trial 156-08-276, Trial 156-13-207 
and Trial 156-12-205).  Informed consent/assent needs to be 
obtained each time a subject matriculates into the next age group. 
j)
ICF and assent, will be obtained from each subject’s parent 
or legal guardian prior to any trial procedures being 
conducted.
k)
Each subject will indicate willingness to participate in the 
trial by signing or marking an assent form (as applicable) 
supplied for this purpose.
2)
Inclusion criteria for entry into the Core Safety Follow-up 
Component will be reviewed.
8)
Body height and body weight will be transferred from the last 
assessments from the previous trial or measured, as appropriate.  
For children ≤ 2 years of age, the assessments cannot be 
transferred. 
9)
Growth percentile will be calculated.  Prior growth development 
information should also be collected, if available.
10) Tanner Staging will be transferred from the last assessments from 
the previous trial or completed as part of the physical 
examination, as appropriate.  Historical staging information 
should also be collected, if available.
11) The final LFT assessments from the previous trial can serve as 
baseline LFT assessments in this trial (see Section 3.7.5.2), as 


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12) Serum sodium will be assessed.
13) Neurocognitive assessments will be performed, as 
appropriate by age and where available, within 
1 hour of the blood draw for serum sodium 
assessment.
14) Quality of Life assessment will be performed, as 
appropriate by age and where available.
15) Concomitant medications will be recorded.
16) Adverse events will be assessed.
appropriate.
12) Serum sodium will be assessed.
13) Neurocognitive assessments will be performed, as appropriate by 
age and where available, within 1 hour of the blood draw for 
serum sodium assessment.
14) Quality of Life assessment will be performed, as appropriate by 
age and where available.
15) Concomitant medications will be recorded.
16) Adverse events will be assessed.
3.7.3.1.3 
Months 2, 4, 
and 6/Early 
Termination:
Subjects will return to the clinical trial site at the end of 
Months 2, 4, and 6 (+ 2 weeks) or at early termination (ET) 
and the following assessments will be performed:
1)
Medical and hyponatremia history will be recorded
separately.  Medical history should include the 
subject’s current list of medical problems in 
addition to the history recorded for the prior trial.  
The hyponatremia medical history should include 
the etiology of subject’s hyponatremia (including 
the tests specified in Section 3.2.2) and what 
treatment was administered before trial enrollment.  
A detailed history specific to etiology of 
hyponatremia will also be recorded.
Subjects will return to the clinical trial site at the end of Months 2, 4, and 
6 (+ 2 weeks) or at early termination (ET) and the following assessments 
will be performed:
1)
Hyponatremia history will be recorded separately.  The 
hyponatremia history should include the etiology of subject’s 
hyponatremia (including the tests specified in Section 3.2.2) and 
what treatment was administered before trial enrollment.  A 
detailed history specific to etiology of hyponatremia will also be 
recorded.
3.7.3.1.3.1 
Additional 
Follow-up 
Contacts:
Section moved from later in the protocol.
Follow-up contacts will occur every 3 months (2 weeks) for all subjects.
1)
Concomitant medications will be recorded.
2)
Adverse events will be assessed.
3.7.3.2 Optional 
Tolvaptan 
Treatment 
Component:
If possible, all assessments while subjects are treated with 
tolvaptan should be synchronized with those performed as 
part of the core safety follow-up component of the trial (ie, 
assessments should not be performed twice at the same time 
If possible, all assessments while subjects are treated with tolvaptan 
should be synchronized with those performed as part of the core safety 
follow-up component of the trial (ie, assessments should not be performed 
twice at the same time point).  Cycles can be repeated based on clinical 


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point).  Cycles can be repeated per clinical need during the 
initial 6 months of the trial and/or after the subject has 
completed the initial 6 months of follow-up.  If a subject is 
off tolvaptan treatment for > 72 hours, titration and 
reinitiation of treatment will require reassessment of the 
eligibility criteria and will begin in a hospital setting.
need during the initial 6 months of the trial and/or after the subject has 
completed the initial 6 months of follow-up.  If a subject is off tolvaptan 
treatment for > 72 hours, titration and reinitiation of treatment will require 
reassessment of the eligibility criteria and will begin in a hospital setting.
3.7.3.2.1 
Pretreatment 
Baseline Visit:
For subjects with a clinical need for tolvaptan treatment, the 
baseline visit for the core safety follow-up component of 
the trial may serve as the pretreatment baseline visit for the 
optional tolvaptan treatment component.  The following 
procedures will be performed during the pretreatment 
baseline visit (Days −4 to −1) to ensure the subject qualifies 
for each tolvaptan treatment cycle:
9)
A serum or urine pregnancy test will be performed 
on female subjects 12 years of age and female 
subjects < 12 years of age if menstruation has 
started.
For subjects with a clinical need for tolvaptan treatment, the following 
procedures will be performed during the pretreatment baseline visit 
(Days −4 to −1) to ensure the subject qualifies for each tolvaptan 
treatment cycle:
9)
A pregnancy test will be performed on female subjects 12 years 
of age and female subjects < 12 years of age if menstruation has 
started.
3.7.3.2.2.1 Day 
1:
1)
Vital signs (blood pressure, heart rate, respiratory 
rate, and temperature) will be assessed after the 
subject has been supine for 3 minutes.  Vital 
signs should be assessed prior to blood draws.
2)
A blood sample for STAT serum sodium testing 
will be collected within 2 to 4 hours prior to 
dosing.  Results need to be reviewed prior to 
dosing to confirm continued treatment eligibility 
of the subject.
3)
Tolvaptan will be administered.
4)
A blood sample for serum sodium testing will be 
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been supine 
for 3 minutes.  Vital signs should be assessed prior to blood 
draws.
2)
A blood sample for STAT serum sodium testing will be collected 
within 2 to 4 hours prior to dosing.  Results need to be reviewed 
prior to dosing to confirm continued treatment eligibility of the 
subject.
3)
In addition to serum sodium samples obtained for treatment 
qualification and efficacy endpoints, supplemental samples for 
the purposes of safety assessment only can be obtained using a 
point of care sodium assessment unit, where available, on Day 1 


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collected 8 hours post-first dose in the current 
treatment cycle.
5)
Concomitant medications will be recorded.
6)
Adverse events will be assessed.
at 4 to 6 hours postdose and at 18 hours postdose.  This sodium 
safety assessment will be repeated at 6 and 18 hours postdose 
each day for the remainder of titration.  A point of care 
assessment unit is preferred; however, regular blood draws may 
be used (especially if they can be combined with standard of care 
labs).
4)
Tolvaptan will be administered.
5)
A blood sample for serum sodium testing will be collected 8 
hours post-first dose in the current treatment cycle.
6)
Concomitant medications will be recorded.
7)
Adverse events will be assessed.
3.7.3.2.2.2 Day 2 
Up to Day 4:
Because each individual’s clinical circumstances differ, the 
investigator will individualize an evaluation scheme for the 
titration period.  The primary evaluation will be that of 
serum sodium concentrations and relevant clinical 
laboratory assessments.  The investigator should schedule 
evaluations daily while the subject remains in a hospital 
setting per the schedule of assessments.  The following 
procedures will be performed during the titration period:
1)
Vital signs (blood pressure, heart rate, respiratory 
rate, and temperature) will be assessed after the 
subject has been supine for 3 minutes.  Vital 
signs should be assessed prior to blood draws.
2)
A blood sample for serum sodium testing must be 
assessed at 24 (4) hours post-previous dose with 
the results reviewed prior to subsequent tolvaptan 
dosing.
3)
Administer tolvaptan.  Tolvaptan will be titrated 
per the titration guidelines (see Section 3.2.1.2) for 
the assigned weight group.
The primary evaluation will be that of serum sodium concentrations and 
relevant clinical laboratory assessments.  The investigator should schedule 
evaluations daily while the subject remains in a hospital setting per the 
schedule of assessments.  The following procedures will be performed 
during the titration period:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been supine 
for 3 minutes.  Vital signs should be assessed prior to blood 
draws.
2)
A blood sample for serum sodium testing must be assessed at 24 
(4) hours post-previous dose with the results reviewed prior to 
subsequent tolvaptan dosing.
3)
In addition to serum sodium samples obtained for treatment 
qualification and efficacy endpoints, supplemental samples for 
the purposes of safety assessment only can be obtained using a 
point of care sodium assessment unit, where available, at 6 and 
18 hours postdose each day for the remainder of titration.  A 
point of care assessment unit is preferred; however, regular blood 
draws may be used (especially if they can be combined with 


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standard of care labs).
4)
Administer tolvaptan.  Tolvaptan will be titrated per the titration 
guidelines (see Section 3.2.1.2) for the assigned weight group.
3.7.3.2.3 Days 7, 
14, and 21:
1)
Vital signs (blood pressure, heart rate, respiratory 
rate, and temperature) will be assessed after the 
subject has been supine for 3 minutes.  Vital 
signs should be assessed prior to blood draws.
2)
A blood sample for serum sodium testing must be 
assessed at 24 (4) hours post-previous dose with 
the results reviewed prior to subsequent tolvaptan 
dosing.
3)
In addition to serum sodium samples obtained for 
treatment qualification and efficacy endpoints, 
supplemental samples for the purposes of safety 
assessment only can be obtained using a point of 
care sodium assessment unit, where available, at 6 
and 18 hours postdose each day for the remainder 
of titration.  A point of care assessment unit is 
preferred; however, regular blood draws may be 
used (especially if they can be combined with 
standard of care labs).
6)
Tolvaptan will be administered.  Subjects and their 
parents/legal guardians will be instructed to return 
any remaining tolvaptan at the next visit for dose 
reconciliation.
4)
Concomitant medications will be recorded.
5)
Adverse events will be assessed.
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been supine 
for 3 minutes.  Vital signs should be assessed prior to blood 
draws.
2)
A blood sample for serum sodium testing must be assessed at 24 
(4) hours post-previous dose with the results reviewed prior to 
subsequent tolvaptan dosing.
7)
Tolvaptan will be administered.  Subjects and their parents/legal 
guardians will be instructed to return any remaining tolvaptan at 
the next visit for dose reconciliation.
3)
Concomitant medications will be recorded.
4)
Adverse events will be assessed.
5)
On Day 21, instruct subjects not to take the Day 30 dose of 
tolvaptan before coming to the clinic on Day 30.
30 (±1) Days 
Post-first Dose:
After 30 days of tolvaptan treatment, all subjects should 
discontinue treatment for assessment of continued need for 
After 30 days of tolvaptan treatment, all subjects (exceptions listed in 
Section 2.1.2) should discontinue treatment for 2 doses to assess the 
continued need for tolvaptan treatment.  Subjects should arrive to the 


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tolvaptan treatment. 
1)
Vital signs (blood pressure, heart rate, respiratory 
rate, and temperature) will be assessed after the 
subject has been supine for 3 minutes.  Vital 
signs should be assessed prior to blood draws.
2)
A blood sample for serum sodium testing must be 
assessed at 24 (4) hours post-previous dose with 
the results reviewed prior to subsequent tolvaptan 
dosing.
3)
A blood sample for ALT, AST, and BT will be 
collected.
8)
Tolvaptan will be administered.
4)
Advise subject to skip the next 2 doses.
5)
Concomitant medications will be recorded.
6)
Adverse events will be assessed.
clinic prior to taking the morning dose of tolvaptan. 
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been supine 
for 3 minutes.  Vital signs should be assessed prior to blood 
draws.
2)
A blood sample for serum sodium testing must be assessed at 24 
(4) hours post-previous dose with the results reviewed prior to 
subsequent tolvaptan dosing.
3)
A blood sample for ALT, AST, and BT will be collected.
4)
Tolvaptan dispensed the previous week will be returned for 
accountability.
9)
Tolvaptan will be administered.
5)
Advise subject to skip the next 2 doses.
6)
Concomitant medications will be recorded.
7)
Adverse events will be assessed.
3.7.3.2.5 Day 31 
(-1):
New section for this amendment
The following assessments will be performed:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been supine 
for 3 minutes.  Vital signs should be assessed prior to blood 
draws.
2)
A clinical status assessment, including a neurological 
examination, will be performed.
3)
A blood sample for serum sodium testing must be assessed a 
minimum of once per day, based on the investigator’s judgment.
4)
Concomitant medications will be recorded.
5)
Adverse events will be assessed.
3.7.3.2.6 Day 32 
(-1):
New section for this amendment
The following assessments will be performed:


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1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been supine 
for 3 minutes.  Vital signs should be assessed prior to blood 
draws.
2)
A clinical status assessment, including a neurological 
examination, will be performed.
3)
A blood sample for serum sodium testing must be assessed a 
minimum of once per day, based on the investigator’s judgment.
4)
Concomitant medications will be recorded.
5)
Adverse events will be assessed.
3.7.3.2.7 Day 33 
(-1):
The following assessments will be performed:
1)
Vital signs (blood pressure, heart rate, respiratory 
rate, and temperature) will be assessed after the 
subject has been supine for 3 minutes.  Vital 
signs should be assessed prior to blood draws.
2)
A clinical status assessment will be performed.
3)
A serum or urine pregnancy test will be performed 
at each visit on female subjects 12 years of age 
and female subjects < 12 years of age if 
menstruation has started.
4)
A blood sample for serum sodium testing must be 
assessed to confirm the need for continuation of 
treatment.  Refer to Figure 3.1-1 and Section 3.2.2
for the trial schematic and a description of the 
treatment continuation decision.
5)
Tolvaptan will be administered if need for 
continued treatment is confirmed. 
Subjects who reinitiate treatment at the same dose 
or a lower dose of tolvaptan after discontinuation 
for up to 72 hours will not be required to reinitiate 
treatment in a hospital setting.  If subjects are off 
tolvaptan treatment for > 72 hours, reinitiation of 
The following assessments will be performed:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been supine 
for 3 minutes.  Vital signs should be assessed prior to blood 
draws.
2)
A clinical status assessment, including a neurological 
examination, will be performed.
3)
A pregnancy test will be performed at each visit on female 
subjects 12 years of age and female subjects < 12 years of age 
if menstruation has started.
4)
A blood sample for serum sodium testing must be assessed to 
confirm the need for continuation of treatment.  Refer to Figure 
3.1-1 and Section Error! Reference source not found. for the 
trial schematic and a description of the treatment continuation 
decision.
5)
Confirm need for continuing treatment.
b)
If continuing treatment is needed and subjects have been off 
drug for up to 72 hours:

Tolvaptan will be administered.  
Subjects who reinitiate treatment at the same dose or a 
lower dose of tolvaptan after discontinuation for up to 


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treatment, starting with titration (Section 3.2.1.2), 
will require reassessment of the eligibility criteria, 
and titration will begin in a hospital setting.  
Tolvaptan should be titrated with regular serum 
sodium assessments.
6)
Concomitant medications will be recorded.
7)
Adverse events will be assessed.
72 hours will not be required to reinitiate treatment in a 
hospital setting.  However, subjects must have a 24 hour 
postdose serum sodium assessment on Day 34 prior to 
being dispensed enough medication to supply them until 
their next on-treatment visit (Section 3.7.3.2.4.4).  
c)
If continuing treatment is needed and subjects have been off 
drug for > 72 hours:

If subjects are off tolvaptan treatment for > 72 hours ( 2 
doses), reinitiation of treatment, starting with titration 
(Section 3.2.1.2), will require reassessment of the 
eligibility criteria, and titration will begin in a hospital 
setting as part of a new treatment cycle starting at the 
pretreatment baseline visit (Section 3.7.3.2.1).  In these 
cases, the new treatment cycle supersedes the follow-up 
visits from the current treatment cycle.
d)
If no continuing treatment is needed:

Complete the assessments for the 7 day post-last dose 
visit (Section 3.7.3.2.7.2).
6)
Concomitant medications will be recorded.
7)
Adverse events will be assessed.
3.7.3.2.8 Day 34 
(-1):
New section for this amendment
The following assessments will be performed:
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been supine 
for 3 minutes.  Vital signs should be assessed prior to blood 
draws.
2)
A clinical status assessment, including a neurological 
examination, will be performed.
3)
A blood sample for serum sodium testing must be assessed.
4)
Tolvaptan will be administered.
5)
Sufficient tolvaptan will be dispensed for subjects that are 
outpatients for QD dosing until their next scheduled visit.  
Subjects and their parents/legal guardians will be instructed to 


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return any remaining tolvaptan at the next visit for dose 
reconciliation.
6)
Concomitant medications will be recorded.
7)
Adverse events will be assessed.
3.7.3.2.9
Treatment 
Cycle Month 2:  
Every 2 Weeks 
(± 2 days):
1)
Vital signs (blood pressure, heart rate, respiratory 
rate, and temperature) will be assessed after the 
subject has been supine for 3 minutes.  Vital 
signs should be assessed prior to blood draws.
2)
A blood sample for serum sodium testing must be 
assessed at 24 (4) hours post-previous dose with 
the results reviewed prior to subsequent tolvaptan 
dosing.
3)
A blood sample for ALT, AST, and BT will be 
collected (at the end of Treatment Cycle Month 2).
4)
For each treatment cycle, a single PK blood 
sample will be collected after 8 consecutive weeks 
of tolvaptan dosing for the determination of 
tolvaptan and metabolites plasma concentrations.
5)
A clinical status assessment will be performed.
6)
A serum or urine pregnancy test will be performed 
at each visit on female subjects 12 years of age 
and female subjects < 12 years of age if 
menstruation has started (at the end of Treatment 
Cycle Month 2 only).
7)
Tolvaptan will be administered.
1)
Vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) will be assessed after the subject has been supine 
for 3 minutes.  Vital signs should be assessed prior to blood 
draws.
2)
A blood sample for serum sodium testing must be assessed at 24 
(4) hours post-previous dose with the results reviewed prior to 
subsequent tolvaptan dosing.
3)
A blood sample for ALT, AST, and BT will be collected (at the 
end of Treatment Cycle Month 2).
4)
For each treatment cycle, a single PK blood sample will be 
collected after 8 consecutive weeks of tolvaptan dosing for the 
determination of tolvaptan and metabolites plasma 
concentrations.
5)
A clinical status assessment will be performed.
6)
A pregnancy test will be performed at each visit on female 
subjects 12 years of age and female subjects < 12 years of age 
if menstruation has started (at the end of Treatment Cycle Month 
2 only).
7)
Tolvaptan dispensed the previous week will be returned for 
accountability.
8)
Tolvaptan will be administered
3.7.3.2.10.1 
Treatment 
Cycle Month 3 
(and every 
month 
thereafter) (± 2 
days):
1)
A serum or urine pregnancy test will be performed 
at each visit on female subjects 12 years of age 
and female subjects < 12 years of age if 
menstruation has started.
2)
A directed physical examination will be 
performed.
1)
A pregnancy test will be performed at each visit on female 
subjects 12 years of age and female subjects < 12 years of age 
if menstruation has started.
2)
A directed physical examination will be performed.
3)
A clinical status assessment will be performed.
4)
A blood sample for ALT, AST, and BT will be collected every 


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3)
A clinical status assessment will be performed.
4)
A blood sample for ALT, AST, and BT will be 
collected every month.
5)
A blood sample for serum sodium testing should 
be taken at each visit.
6)
Tolvaptan will be administered.
7)
Sufficient tolvaptan will be dispensed for subjects 
that are outpatients for QD dosing until their next 
scheduled visit.  Subjects and their parents/legal 
guardians will be instructed to return any 
remaining tolvaptan at the next visit for dose 
reconciliation.
8)
If a PK sample has not been taken at the end of the 
Treatment Cycle Month 2 visits, a single PK blood 
sample will be collected after 8 consecutive weeks 
of tolvaptan dosing for the determination of 
tolvaptan and metabolites plasma concentrations.
9)
Concomitant medications will be recorded.
10) Adverse events will be assessed.
Tolvaptan treatment cycles may be repeated per a subject’s 
clinical need and the discretion of the investigator.  Subjects 
may be evaluated for continued need for tolvaptan 
treatment at additional clinical trial site visits per the 
investigator’s discretion.  After discontinuation of 
tolvaptan, serum sodium concentrations will be assessed at 
24 (4) hours and at 7 (+ 1) days post-last dose. 
month.
5)
A blood sample for serum sodium testing should be taken at each 
visit.
6)
Tolvaptan dispensed the previous week will be returned for 
accountability.
7)
Tolvaptan will be administered.
8)
Sufficient tolvaptan will be dispensed for subjects that are 
outpatients for QD dosing until their next scheduled visit.  
Subjects and their parents/legal guardians will be instructed to 
return any remaining tolvaptan at the next visit for dose 
reconciliation.
9)
If a PK sample has not been taken at the end of the Treatment 
Cycle Month 2 visits, a single PK blood sample will be collected 
after 8 consecutive weeks of tolvaptan dosing for the 
determination of tolvaptan and metabolites plasma 
concentrations.
10) Concomitant medications will be recorded.
11) Adverse events will be assessed.
Tolvaptan treatment cycles may be repeated per a subject’s clinical need 
and the discretion of the investigator.  Subjects may be evaluated for 
continued need for tolvaptan treatment at additional clinical trial site visits 
per the investigator’s discretion.  After discontinuation of tolvaptan, serum 
sodium concentrations will be assessed at 24 (4) hours and at 7 (+ 1) 
days post-last dose.  Subjects who elect to opt out of treatment within a 
treatment cycle should immediately proceed to the Follow-up Phase.
3.7.3.2.11.1 
First Follow-up: 
24 (± 4) hours 
post-last dose:
3)
A serum or urine pregnancy test will be performed 
on female subjects 12 years of age and female 
subjects < 12 years of age if menstruation has 
started (if not done within the last 30 days).
3)
A pregnancy test will be performed on female subjects 12 years 
of age and female subjects < 12 years of age if menstruation has 
started (if not done within the last 30 days).


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3.7.4.1.1 
Pretreatment 
Baseline Visit:
All subjects should have blood samples collected for serum 
sodium assessment at the baseline visit or transferred from 
the last visit of the previous trial.  Within 48 hours prior to 
tolvaptan administration, 2 blood samples will be collected 
at least 12 hours apart for assessment of baseline serum 
sodium to determine subject eligibility for tolvaptan 
treatment.  A third serum sodium sample should be drawn 
within 2 to 4 hours prior to dosing; the results must be 
verified to be < 130 mEq/L (mmol/L) prior to the first dose 
in each treatment cycle.
All subjects should have blood samples collected for serum sodium 
assessment at a prior visitor transferred from the last visit of the previous 
trial.  Within 48 hours prior to tolvaptan administration, 2 blood samples 
will be collected at least 12 hours apart for assessment of baseline serum 
sodium to determine subject eligibility for tolvaptan treatment.  A third 
serum sodium sample (STAT) should be drawn within 2 to 4 hours prior 
to dosing; the results must be verified to be < 130 mEq/L (mmol/L) prior 
to the first dose in each treatment cycle.
3.7.4.1.2 Initial 
Titration Phase 
and Month 1:
During the Titration Phase (the first 30 days of treatment) 
subjects should have serum sodium assessments at a 
minimum of QD on Day 1 up to  Day 4 of treatment, and at 
a minimum of once weekly thereafter (ie, on Days 7, 14, 
21, and 28 of Month 1).  On Day 1, a serum sodium sample 
should be collected STAT and recorded in the CRF at a 
minimum of 8 hours post-first dose and 24 (4) hours 
post-previous dose. 
During the Titration Phase (the first 30 days of treatment) subjects should 
have serum sodium assessments at a minimum of QD on Day 1 up to  Day 
4 of treatment, and at a minimum of once weekly thereafter (ie, on Days 7, 
14, 21, and 28 of Month 1).  On Day 1, a serum sodium sample should be 
collected STAT and recorded in the CRF at a minimum of 8 hours 
post-first dose and 24 (4) hours post-previous dose. 
In addition to serum sodium samples obtained for treatment qualification 
and efficacy endpoints, supplemental samples for the purposes of safety 
assessment only can be obtained using a point of care sodium assessment 
unit, where available, on Day 1 at 4 to 6 hours postdose and at 18 hours 
postdose.  This sodium safety assessment will be repeated at 6 and 18 
hours postdose each day for the remainder of titration.  A point of care 
assessment unit is preferred; however, regular blood draws may be used 
(especially if they can be combined with standard of care labs).
3.7.4.2 Quality 
of Life 
AssessmentsL
The assessment time points are at Baseline, Month 2, 
Month 4, and at Month 6 or Early Termination during the 
The assessment time points during the Core Safety Follow-up Component 
are at Baseline, Month 2, Month 4, and at Month 6 or Early Termination.


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Core Safety Follow-up Component.
3.7.5.2 Clinical 
Laboratory 
Tests: Core 
Safety Follow-
up Component:
For all subjects enrolled in the core safety follow-up 
component, serum sodium assessments and LFTs will either 
be performed at baseline or transferred from the last visit of 
the previous trial.  At Months 2, 4, and 6, serum sodium 
will be assessed.  At Month 2 or at ET, if ET occurs before 
the Month 2 Visit, ALT, AST, and BT will be measured.  
No further laboratory assessments are required per protocol 
except as needed for the follow-up of AEs.
For all subjects enrolled in the core safety follow-up component, LFT 
assessments will either be performed at baseline or transferred from the 
last visit of the previous trial, as long as not more than 1 month prior to 
previous trial.  Serum sodium assessment is required during the baseline 
visit in the Core Safety Follow-up Component.  At Months 2, 4, and 6, 
serum sodium will be assessed.  At Month 2 or at ET, if ET occurs before 
the Month 2 Visit, ALT, AST, and BT will be measured.  No further 
laboratory assessments are required per protocol except as needed for the 
follow-up of AEs.
3.7.5.3 Clinical 
Laboratory 
Tests: Optional 
Tolvaptan 
Treatment 
Component:
If these results are to be obtained as part of the standard of 
care for the subject, the timing should be coordinated per 
the schedule of assessments (Section 3.7.3), whenever 
possible, to minimize the number of blood draws for the 
subject while at the same time ensuring that liver 
function tests are monitored on a monthly basis while 
continuing treatment with tolvaptan.
If these results are to be obtained as part of the standard of care for the 
subject, the timing should be coordinated per the schedule of assessments 
(Section 3.7.3), whenever possible, to minimize the number of blood 
draws for the subject while at the same time ensuring that liver 
function tests are monitored on a monthly basis while continuing 
treatment with tolvaptan.  For the schedule of laboratory assessments, 
please refer to Appendix 6.
Table 3.7.5.3-1:
Clinical Laboratory Tests During Tolvaptan Treatment
Clinical Laboratory Tests During Optional Tolvaptan Treatment
3.7.5.5 Tanner 
Staging:
The collection of Tanner Staging data is required for all 
subjects in the core safety follow-up component at the 
Month 6 Visit.  Every attempt should be made to collect 
this information.
...A subject who reaches Stage 5 (both in pubic hair and 
genitalia) does not need to continue with Tanner Staging.  
The collection of Tanner Staging data is required for all subjects in the 
core safety follow-up component at the baseline and the Month 6 Visit.  
Every attempt should be made to collect this information. 
...A subject who reaches Stage 5 (both in pubic hair and genitalia) does 
not need to continue with Tanner Staging and the same stage will be 
carried forward to any subsequent visits.  
3.7.5.6 
Hyponatremia 
Each subject’s hyponatremia medical history will be 
recorded at baseline.  The hyponatremia history should 
Each subject’s hyponatremia medical history will be recorded at the 
baseline visit of the core safety follow-up component as well as at the pre-


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History:
include the etiology of subject’s hyponatremia (including 
tests per protocol) and what treatment was administered 
before trial enrollment.  Symptoms potentially attributable 
to hyponatremia should be specifically assessed for prior 
history.  The hyponatremia assessment at baseline will 
consist of documentation of hyponatremia etiology (eg, 
SIADH, hepatocellular disease [including cirrhosis], heart 
failure, or other) prior fluid intake and output, and prior 
hyponatremia treatment, ie, fluid restriction, if applicable.  
A detailed history specific to etiology of hyponatremia will 
also be recorded.
treatment baseline visit of the optional tolvaptan component.  The 
hyponatremia history should include the etiology of subject’s 
hyponatremia (including tests per protocol) and what treatment was 
administered before trial enrollment.  Symptoms potentially attributable to 
hyponatremia should be specifically assessed for prior history.  The 
hyponatremia assessment at baseline will consist of documentation of 
hyponatremia etiology (eg, SIADH, hepatocellular disease [including 
cirrhosis], heart failure, or other) prior fluid intake and output, and prior 
hyponatremia treatment, ie, fluid restriction, if applicable.  A detailed 
history specific to etiology of hyponatremia will also be recorded.
3.7.6.1 Blood 
Collection 
Times:
For subjects undergoing treatment with tolvaptan for at 
least 8 consecutive weeks for each initiation or reinitiation 
of therapy, a single blood sample to measure tolvaptan and 
metabolite concentrations at steady state will be obtained 
for each cycle.  The date and time of the PK sample and the 
date and time of the dose given immediately prior to the PK 
sample will be recorded on the CRFs.
For each subject all samples will be collected according to 
local guidelines and best practices for pediatric care.  If a 
sample is missing because of limitations in allowable blood 
volumes based on local regulations or local practice this 
will not count as a protocol deviation.
For subjects undergoing treatment with tolvaptan for at least 8 consecutive 
weeks (short interruptions of < 72 hours is still considered consecutive 
treatment) for each initiation or reinitiation of therapy, a single blood 
sample to measure tolvaptan and metabolite concentrations at steady state 
will be obtained for each cycle.  The date and time of the PK sample and 
the date and time of the dose given immediately prior to the PK sample 
will be recorded on the CRFs.
For each subject all samples will be collected according to local guidelines 
and best practices for pediatric care.
3.7.9 
Independent 
Data 
Monitoring 
Committee:
New section for this amendment
An independent data monitoring committee (IDMC) will be established 
for this trial.  This committee will meet on a regular basis to ensure the 
safe and ethical treatment of trial subjects, ensure the scientific integrity of 
the trial, and to ensure the trial is conducted within the bounds of ethical 


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medical practice.  It may make recommendations to the sponsor and trial 
steering committee to amend or terminate the trial based on grounds of 
safety, futility, or greater than expected efficacy as defined by the 
accepted statistical practices and procedures to be detailed in their charter.  
The specific duties of the IDMC will be detailed in a separate IDMC 
charter document.
3.8.3 Individual 
Subject:
...In addition, subjects on tolvaptan treatment who meet the 
following criteria should have results confirmed with a 
repeat test. 
...If subjects consent, the investigator will continue to 
contact those who discontinue tolvaptan every 3 months 
through the final completion date of the trial or thereafter if
needed to determine outcomes ie, vital status.
...In addition, subjects on tolvaptan treatment who meet the following 
criteria should have results confirmed with a repeat test.  Sodium tests 
should be done either STAT or through bedside monitoring.
...If subjects consent, the investigator will continue to contact those who
stop tolvaptan treatment and those who complete the Core Safety Follow-
up Component every 3 months through the final completion date of the 
trial or thereafter if needed to determine outcomes ie, vital status.
...When a subject or parent/legal guardian or legally responsible 
representative decides to withdraw from the trial they will be asked to 
indicate whether they wish to discontinue from the trial as a whole (Core 
Safety Follow-up Component and Optional Treatment Component, as 
applicable), or to discontinue trial visits in the Core Safety Follow-up 
Component while still allowing for telephone contacts, or ( if enrolled in 
the Optional Treatment Component) to withdraw from IMP while still 
continuing in the Core Safety Follow-up Component.
3.8.3 Individual 
Subject:
The investigator will notify the sponsor promptly when a 
subject is withdrawn.
The investigator will notify the sponsor promptly when a subject is 
withdrawn.
If subjects consent, the investigator will continue to contact those who
discontinue tolvaptan every 3 months through the final completion date of 
the trial or thereafter if needed to determine outcomes ie, vital status.


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3.10 Definition 
of Completed 
Subjects:
...Any visits beyond the Month 6 Visit will be considered 
“follow-up” visits for the purpose of evaluating safety and 
efficacy for those subjects who require treatment with 
tolvaptan.
Prior to the end of the trial, each subject’s final visit should 
be documented, including the date of the last dose and the 
number of treatment cycles.
...Any visits beyond the Month 6 Visit will be considered “follow-up” 
visits for the purpose of evaluating safety and efficacy for those subjects 
who require treatment with tolvaptan and safety for those subjects who do 
not receive treatment.
Upon the sponsor’s decision to terminate the trial, each subject’s final visit 
should be documented, including the date of the last dose and the number 
of treatment cycles.  The core safety follow-up component of the trial is 
expected to continue until all enrolled subjects from Trials 156-08-276, 
156-13-207, or 156-12-205 have been followed for 6 months.  For subjects 
in the optional tolvaptan treatment component, the length of participation 
for each individual subject will vary depending on duration of treatment 
required and the need for repeated treatments.  The opportunity to 
participate in the Optional Tolvaptan Treatment Component is planned to 
remain open until the last subject completes the Core Safety Follow-up 
Component.
4.1 Prohibited 
Medications:
...Since tolvaptan is a weak CYP3A4 substrate, subjects 
weighing 20 kg and taking moderate inhibitors of 
CYP3A4 will be administered a half-dose of tolvaptan.  
...Since tolvaptan is a sensitive CYP3A4 substrate, subjects weighing 20 
kg and taking moderate inhibitors of CYP3A4 will be administered a 
half-dose of tolvaptan.  
4.2 Other 
Restrictions:
The use of saline in this population should be closely 
monitored.  The use of hypertonic saline (3% or greater) 
within 8 hours of the initial screening laboratory collection 
prior to tolvaptan treatment is prohibited.  The use of 
hypertonic saline (3% or greater) is highly discouraged
during tolvaptan treatment.  Please see Section 4.1 for the 
list of prohibited medications during tolvaptan treatment.  
The use of normal saline (0.9%) is allowed during the 
Pretreatment baseline Period until the beginning of 
The use of saline in this population should be closely monitored.  The use 
of hypertonic saline (3% or greater) within 8 hours of the initial screening 
laboratory collection prior to tolvaptan treatment is prohibited.  The use of 
hypertonic saline (3% or greater) is prohibited during tolvaptan treatment.  
Routine use of hypertonic saline, while prohibited, may be considered 
only if used emergently (ie, with a severe symptomatic episode) and with 
the understanding that free water clearance may be stimulated if tolvaptan 
had been administered in the prior 24 hours, based on the medical 
judgment of the investigator.  Please see Section 4.1 for the list of 


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treatment; normal saline use can resume during the follow-
up period.  Subjects should no longer be on maintenance 
fluids containing normal saline during treatment with 
tolvaptan.  Subjects may be administered IV solutions 
containing hypotonic saline (eg, half-normal [0.45%] 
saline) if necessary, for fluid management.  The medical 
monitor should be contacted at any point if questions arise 
regarding the use of saline during the trial.
prohibited medications during tolvaptan treatment.  The use of normal
saline (0.9%) is allowed during the Pretreatment baseline Period until the 
beginning of treatment; normal saline use can resume during the follow-up 
period.  Subjects should no longer be on maintenance fluids containing 
normal saline during treatment with tolvaptan.  Subjects may be 
administered IV solutions containing hypotonic saline (eg, half-normal 
[0.45%] saline) if necessary, for fluid management.  The medical monitor 
should be contacted at any point if questions arise regarding the use of 
saline during the trial.
5.4.1.1 Criteria 
for 
Discontinuation 
From the 
Optional 
Tolvaptan 
Treatment 
Component of 
the Trial due to 
Liver 
Transaminase 
Elevations:
...If there is any question about how to proceed with a 
particular subject’s case, do not hesitate to contact your 
regional medical monitor to discuss it.  
...If there is any question about how to proceed with a particular subject’s 
case, do not hesitate to contact your regional medical monitor to discuss 
treatment options.  
5.5 Pregnancy:
Female subjects of childbearing potential who are sexually 
active must use an effective method of birth control during 
the course of the trial and for 14 days after the last dose of 
IMP in a manner such that risk of failure is minimized.  
Unless the subject or her partner(s) is sterile (ie, female 
subjects who have had an oophorectomy and/or 
hysterectomy; or male partners who have had orchiectomy) 
or remain abstinent, two of the following precautions must 
Women of childbearing potential (WOCBP) are defined as female subjects 
for whom menstruation has started and who are not documented as sterile 
(ie, have had a bilateral oophorectomy and/or hysterectomy or who have 
been postmenopausal for at least 12 months).
For WOCBP who are sexually active, 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 


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be used:  vasectomy, tubal ligation, vaginal diaphragm, 
intrauterine device, birth control pills, birth control depot 
injection, birth control implant, condom, or sponge with 
spermicide.  Any single method of birth control, including 
vasectomy and tubal ligation, may fail, leading to 
pregnancy.
Before enrolling female subjects of childbearing potential 
in this clinical trial, investigators must review guidelines 
about trial participation for female subjects of childbearing 
potential.  The topics should generally include:

General information

ICF/assent form, as applicable

Pregnancy prevention information

Drug interactions with hormonal 
contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported 
pregnancy
Prior to trial enrollment, female subjects of childbearing 
potential must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk 
factors for an unintentional pregnancy.  The subject’s 
parent or legal guardian must sign an ICF stating that the 
above-mentioned risk factors and the consequences were 
discussed with the subject and parent/guardian.
During the trial, all female subjects of childbearing 
sterile (ie, women who have had a bilateral oophorectomy and/or 
hysterectomy or who have been postmenopausal for at least 12 
consecutive months) or remains fully abstinent (periodic abstinence [eg, 
calendar, ovulation, symptothermal, post-ovulation methods] or 
withdrawal are not acceptable methods of contraception), two of the 
following precautions must be used:  vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth control pills, birth control depot 
injection, birth control implant, condom with spermicide, or sponge 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.
Before enrolling WOCBP in this clinical trial, investigators must review 
the below guidelines about trial participation with all WOCBP.  The topics 
should generally include:

General information

ICF/assent form, as applicable

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, WOCBP must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk factors 
for an unintentional pregnancy.  The subject or the subject’s parent or 
legal guardian must sign an ICF stating that the above-mentioned risk 
factors and the consequences were discussed with the subject and/or the 


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potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (eg, 
missed or late menstrual cycle).
If a subject or investigator suspects that the subject may be 
pregnant prior to IMP administration, the IMP 
administration must be withheld until the results of serum 
pregnancy tests are available.  If the pregnancy is 
confirmed, the subject must be withdrawn from the trial.  If 
pregnancy is suspected while the subject is taking IMP, the 
IMP must be withheld immediately (if reasonable, taking 
into consideration any potential withdrawal risks) until the 
result of the pregnancy is known.  If pregnancy is 
confirmed, the IMP will be permanently discontinued in an 
appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the 
trial.  (Exceptions to trial discontinuation may be 
considered for life-threatening conditions only after 
consultations with the trial medical monitor.)
The investigator must immediately notify INC Research of 
any pregnancy associated with IMP exposure, including 
14 days after the last dose of IMP and record the event on 
the IRE form and forward it to INC Research.  INC 
Research will forward Pregnancy Surveillance Form(s) for 
monitoring the outcome of the pregnancy.
Protocol-required procedures for trial discontinuation and 
follow-up must be performed on the subject unless 
contraindicated by pregnancy (eg, x-ray trials).  Other 
parent/guardian.
A urine and/or serum pregnancy test for human chorionic gonadotropin 
(hCG) will be performed at screening on all WOCBPand female subjects 
≥12 years of age and all female subjects < 12 years of age, if menstruation 
has started.  If a urine test is performed and is positive, the investigator 
will follow up with a confirmatory serum test.
During the trial, all WOCBP should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (eg, 
missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP 
administration must be withheld until the results of serum pregnancy tests 
are available.  If the pregnancy is confirmed, the subject must not receive 
the IMP and must not be enrolled in the trial.  If pregnancy is suspected 
while the subject is taking IMP, the IMP must be withheld immediately (if 
reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety) and the subject will be withdrawn 
from the trial.  (Exceptions to trial discontinuation may be considered for 
life-threatening conditions only after consultations with the Clinical Safety 
and Pharmacovigilance department [see Appendix 1 for contact 
information])
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.


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appropriate pregnancy follow-up procedures should be 
considered if indicated.  In addition, the investigator must 
report to INC Research, 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.
Protocol-required procedures for trial discontinuation and follow-up must 
be performed on the subject unless contraindicated by pregnancy (eg, x-
ray trials).  Other appropriate pregnancy follow-up procedures should be 
considered, if indicated.  In addition, 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.
9.1 Source 
Documents:
...Investigator(s)/institution(s) will permit trial-related 
monitoring, audits, IRB/IEC review, and regulatory 
inspection(s) by providing direct access to source 
data/documents by authorized persons as defined in the 
ICF.
...Investigator(s)/institution(s) will permit trial-related monitoring, audits, 
IRB/IEC review, and regulatory inspection(s) by providing direct access 
to source data/documents by authorized persons as defined in the ICF.  In 
all cases, subject confidentiality must be maintained in accordance with 
local regulatory requirements.
9.2 Data 
Collection:

Documentation of the informed consent process, 
including any revised consents;

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, and duration of any AEs and the 
investigator's assessment of relationship to 
tolvaptan 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 all clinicians 
who made an entry in the progress notes.

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 
tolvaptan 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 tolvaptan 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.


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...Changes will be made by striking a single line through 
erroneous 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 clinician.
...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 clinician.  If electronic data systems are being 
utilized, a full audit trail of changes must be maintained.
9.3 File 
Management at 
the Trial Site:
The investigator will ensure that the trial center file is 
maintained in accordance with Section 8 of the ICH 
Guideline for GCP and as required by applicable local 
regulations.
The investigator 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.  
9.4 Records 
Retention at the 
Trial Site:

A period of at least 2 years following the date on 
which approval to market the drug is obtained (or 
if tolvaptan development is discontinued, the date 
of discontinuation); OR
...The investigator will be responsible to maintain adequate 
and accurate electronic or hard copy source documents of 
all observations and data generated during this trial.  

A period of at least 2 years following the date on which approval 
to market the drug is obtained (or if tolvaptan development is 
discontinued, the date regulatory authorities were notified of 
discontinuation); OR
...The investigator 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.  
10.1 
Monitoring:
The sponsor has ethical, legal, and scientific obligations to 
follow this trial carefully in a detailed and orderly manner 
in accordance with established research principles, the ICH 
GCP Guideline, and applicable regulatory requirements and 
local laws.  As part of a concerted effort to fulfill these 
obligations (maintain current personal knowledge of the 
progress of the trial), the sponsor's monitors will visit the 
site during the trial, as well as communicate frequently via 
The sponsor has ethical, legal, and scientific obligations to follow this trial 
in accordance with established research principles, the ICH E6 GCP: 
Consolidated Guidance, and applicable regulatory requirements and local 
laws.  As part of a concerted effort to fulfill these obligations (maintain 
current personal knowledge of the progress of the trial), the sponsor's 
monitors will visit the site during the trial, as well as communicate 
frequently via telephone, e-mail, and written communications.  In 
addition, all investigators and clinical site personnel will undergo initial 


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telephone and written communications.
and ongoing training for this particular trial, and this training will be 
clearly documented.
10.2 Auditing:
The sponsor's Quality Management Unit (or representative) 
may conduct trial site audits.  Audits will include but are 
not limited to drug supply, presence of required documents, 
the informed consent process, and comparison of CRFs 
with source documents.  
The sponsor's Quality Assurance Unit (or representative) may conduct 
trial site audits.  Audits will include, but are not limited to, drug supply, 
presence of required documents, the informed consent process, and 
comparison of CRFs with source documents.  
11 Ethics and 
Responsibility:
This trial must be conducted in compliance with the 
protocol, the ICH GCP Guideline, and applicable local laws 
and regulatory requirements.  Each trial site will seek 
approval by an IRB or IEC according to regional 
requirements.  
This trial must be conducted in compliance with the protocol, the ICH 
GCP Guideline (E6), international ethical principles derived from the 
Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) guidelines, and applicable local laws and 
regulations.  Each trial site will seek approval/favorable opinion by an 
IRB or IEC according to regional requirements, and the investigator will 
provide that documentation to the sponsor.  
12 
Confidentiality:
...However, authorized regulatory officials and sponsor 
personnel (or their representatives) will be allowed full 
access to inspect and copy the records.  All supplies of 
tolvaptan, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this 
protocol, unless otherwise agreed to in writing by the 
sponsor.
Subjects will be identified only by initials and unique 
subject numbers in CRFs.  Their full names may, however, 
be made known to a regulatory agency or other authorized 
officials if necessary.
...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 supplies of tolvaptan, 
subject bodily fluids, and/or other materials collected shall be used solely 
in accordance with this protocol, unless otherwise agreed to in writing by 
the sponsor.
Subjects will be identified only by unique subject numbers 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.


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13 Amendment 
Policy:
The investigator will not make any changes to this protocol 
without the sponsor’s prior written consent and subsequent 
approval by the IRB/IEC.  Any permanent change to the 
protocol, whether it be 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/IEC.  Except for “administrative” or “non-substantial” 
amendments, investigators will wait for IRB/IEC approval 
of the amended protocol before implementing the 
change(s).  Administrative amendments are defined as 
having no effect on the safety of subjects, conduct or 
management of the trial, trial design, or the quality or safety 
of the tolvaptan tablets used in the trial.  A protocol change 
intended to eliminate an apparent immediate hazard to 
subjects should be implemented immediately, followed by 
IRB/IEC notification within 5 working days.  The sponsor 
will submit protocol amendments to the applicable 
regulatory agencies.
When the IRB/IEC, 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, repeat informed 
consent will be obtained from subjects enrolled in the trial 
before expecting continued participation.
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/IEC.  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/IEC, as required by local 
regulations.  Except for “administrative” or “non-substantial” 
amendments, investigators will wait for IRB/IEC 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 the tolvaptan tablets used in the trial.  A protocol change 
intended to eliminate an apparent immediate hazard to subjects should be 
implemented immediately after agreement by the sponsor and investigator, 
followed by IRB/IEC notification within local applicable timelines.  The 
sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
When the IRB/IEC, 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/IEC, 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 
New section for this amendment


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Requirements:
Appendix 2:
Medical Monitor:
 INC Research
580 Union Square Drive
New Hope, Pennsylvania 18938 US
Phone 
 Mobile 
E-Mail 
Medical Monitor:
3210 Beechleaf Ct., Suite 600
Raleigh, North Carolina 27604, USA
Phone 
 Mobile 
Fax:  
E-Mail: 
Appendix 2:
New contact information added with this amendment.
IDMC Support
Theorem Clinical Research
1016 West Ninth Avenue
King of Prussia, PA, 19406, USA
Phone:  
Fax:  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Old Text:  Appendix 5
Optional Tolvaptan Treatment Component:  Eligibility Criteria
Subjects will be eligible for tolvaptan treatment if they meet the criteria outlined in the table below.
Eligibility Criteria for Optional Tolvaptan Treatment
1.
Male or female subjects 4 weeks (or 44 weeks adjusted gestational age) to < 18 years old
2.
The subject must have been off treatment with the investigational medicinal product (IMP) for 7 days following the 
end of treatment in the previous trial of titrated oral IMP (tolvaptan in Trial 156-08-276, tolvaptan or placebo in 
Trials 156-13-207 and 156-12-205) to assess the subject’s clinical need for dosing
3.
Persistent dilutional (euvolemic or hypervolemic hyponatremia) defined as being documented as present for at least 
48 hours, evidenced by at least 2 serum sodium assessments < 130 mEq/L (mmol/L) drawn at least 12 hours apart 
(these values can be documented using historical values previously obtained per standard of care); a third (STAT) 
serum sodium assessment < 130 mEq/L (mmol/L), which will serve as the baseline value for efficacy endpoints, is to 
be obtained within 2 to 4 hours prior to the first dose of tolvaptan
4.
Ability to take oral medication
5.
Ability to maintain adequate fluid intake whether orally or via IV support with adequate monitoring
6.
Ability to comply with all requirements of the trial
7.
Trial-specific written informed consent/assent obtained from a parent/guardian or legally acceptable representative, 
as applicable per age of subject or local laws, prior to the initiation of any protocol-required procedures.  In addition, 
the subject as required by local laws must provide informed assent at the pretreatment baseline for this trial and must 
be able to understand that he or she can withdraw from the trial at any time.  All informed consent/assent procedures 
must be in accordance with the trial center’s IRB/IEC and local regulatory requirements
8.
Ability to commit to remain abstinent or practice double-barrier birth control during the trial and for 14 days 
following the last dose of tolvaptan for sexually active females of childbearing potential
Subjects will be ineligible for tolvaptan treatment if they meet any of the following criteria:
Ineligibility Criteria for Tolvaptan Treatment
25.
Subjects < 2 years of age, weight <10 kg, or who cannot swallow an oral tablet are excluded until an oral liquid 
formulation becomes available


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New Text:  Appendix 5 
Optional Tolvaptan Treatment Component:  Eligibility Criteria
Subjects will be eligible for tolvaptan treatment if they meet the criteria outlined in the table below.
Eligibility Criteria for Optional Tolvaptan Treatment
1.
Male or female subjects 4 weeks (or 44 weeks adjusted gestational age)
2.
The subject must have been off treatment with the investigational medicinal product (IMP) for at least 
7 days following the end of treatment in the previous trial of titrated oral IMP (tolvaptan in 
Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 156-12-205) to assess the subject’s 
clinical need for dosing
3.
Persistent dilutional (euvolemic or hypervolemic) hyponatremia defined as being documented as present 
for at least 48 hours, evidenced by at least 2 serum sodium assessments < 130 mEq/L (mmol/L) drawn at 
least 12 hours apart (these values can be documented using historical values previously obtained per 
standard of care); a third (STAT) serum sodium assessment < 130 mEq/L (mmol/L), which will serve as 
the baseline value for efficacy endpoints, is to be obtained within 2 to 4 hours prior to the first dose of
tolvaptan
4.
Ability to take oral medication
5.
Ability to maintain adequate fluid intake whether orally or via IV support with adequate monitoring
6.
Ability to comply with all requirements of the trial
7.
Trial-specific written informed consent/assent obtained from a parent/guardian or legally acceptable 
representative, as applicable per age of subject or local laws, prior to the initiation of any protocol-required 
procedures. In addition, the subject as required by local laws must provide informed assent at the 
pretreatment baseline for this trial and must be able to understand that he or she can withdraw from the trial 
at any time.  All informed consent/assent procedures must be in accordance with the trial center’s IRB/IEC 
and local regulatory requirements
8.
Ability to commit to remain fully abstinent (periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] or withdrawal are not acceptable methods of contraception) or practice double-
barrier birth control during the trial and for 30 days following the last dose of tolvaptan for sexually active 
females of childbearing potential
Ineligibility Criteria for Tolvaptan Treatment
25.
Subjects < 2 years of age, weight < 10 kg, or who cannot swallow an oral tablet are excluded until an 
alternate formulation becomes available


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Old Text:  Appendix 6
Optional Tolvaptan Treatment Component:  Laboratory Assessment Schedule
Frequency of Recurring Laboratory Assessments
Treatment Phase
Serum Sodium
LFTs 
(ALT, AST, BT)
PKa
Pretreatment Baseline 
doses
Day -1 to Day -4: 
assessments 130 mEqL 
(mmol/L) 12 hours apart
Month 1: Titrationb
Once daily
Month 6, End of 
Treatment or Early 
Termination
24 (4) hours and 7 (1) 
days
New Text:  Appendix 6
Optional Tolvaptan Treatment Component:  Laboratory Assessment Schedule
Frequency of Recurring Laboratory Assessments
Treatment Phase
Serum Sodium
LFTs 
(ALT, AST, BT)
PKa
Pretreatment Baseline 
doses
Day -1 to Day -4: 
assessments 130 mEqL 
(mmol/L) 12 hours apart
Required at 
Baseline if not 
done within the 
previous month
Month 1: Titrationb
Once daily efficacy 
assessment and additional  
safety assessments 4 to 6 
hours and 18 hours postdose
Post-last dose Follow-up 
each cycle
24 (4) hours and 7 (1) 
days


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Agreement:
...and in the sponsor's (or designee's) Clinical Research 
Agreement.
...I am aware that this protocol must be approved by the 
Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) responsible for such matters in the 
clinical trial facility where tolvaptan will be tested prior 
to commencement of this trial.  I agree to adhere strictly 
to the attached protocol (unless amended in the manner 
set forth in Paragraph I of the sponsor's Clinical 
Research Agreement, at which time I agree to adhere 
strictly to the protocol as amended).
...I agree to await IRB/IEC approval before 
implementation of any protocol amendments to this 
protocol.  If, however, there is an immediate hazard to 
subjects, I will implement the amendment immediately, 
and provide the information to the IRB/IEC within 5 
working days.  Administrative changes to the protocol 
will be transmitted to the IRB/IEC for informational 
purposes only.
...I agree to report to the sponsor any adverse 
experiences in accordance with the terms of the 
sponsor's Clinical Research Agreement and the relevant 
regional regulation(s) and guideline(s).  I further agree 
to provide all required information regarding financial 
certification or disclosure to the sponsor for all 
investigators and sub-investigators in accordance with 
the terms of the relevant regional regulation(s).  I 
...and in the sponsor's (or designee's) Clinical Trial Agreement.
...I am aware that this protocol must be approved by the Institutional Review 
Board (IRB) or receive a favorable opinion by the Independent Ethics 
Committee (IEC) responsible for such matters in the clinical trial facility 
where tolvaptan will be tested prior to commencement of this trial.  I agree to 
adhere strictly to the attached protocol (unless amended in the manner set forth 
in the sponsor's Clinical Trial Agreement, at which time I agree to adhere 
strictly to the protocol as amended).
...I agree to await IRB/IEC approval before implementation of any substantial 
amendments to this protocol.  If, however, there is an immediate hazard to 
subjects, I will implement the amendment immediately, and provide the 
information to the IRB/IEC within the required local applicable timelines.  
Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations.
...I agree to report to the sponsor any adverse experiences in accordance with 
the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s).  I further agree to provide all required 
information regarding financial certification or disclosure to the sponsor for all 
investigators and sub-investigators in accordance with the terms of the relevant 
regional regulation(s).  I understand that participation in the protocol involves 
a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may 
occur, and I consent to be acknowledged in any such cooperative publications 
that result.
____________________________
Principal Investigator 


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understand that participation in the protocol involves a 
commitment to publish the data from this trial in a 
cooperative publication prior to publication of efficacy 
and safety results on an individual basis.
_____________________________________________
Principal or Coordinating Investigator Signature and 
Date
_____________________________________________
Sponsor Representative Signature and Date
____________________________
Print Name
____________________________
Signature
____________________________
Date
ADDITIONAL RISK TO THE SUBJECT:  There is no additional risk to the subjects.


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Amendment Number:
3
Issue Date:
9 November 2015
PURPOSE:
The main intent of the amendment is to streamline text within the protocol by providing 
administrative clarifications, removing duplicative language, and ensuring consistency 
across sections.  Efficiencies have been established in the Schedule of Assessments 
between the core safety and optional tolvaptan treatment components.  This amendment 
is also intended to reduce burden on the subject, including the replacement of Months 2 
and 4 in-clinic visits with telephone assessments.  Therefore assessments required for 
in-clinic visits on these months have been removed.  
BACKGROUND
This is a pediatric trial required by the EMA under the Pediatric Investigational Plan 
(PIP).  The changes implemented within this protocol amendment continue to address the 
key binding elements of the PIP.
GENERAL CHANGES:


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Description of Change
Rationale for Change
Sections Affected by Change
General Changes
Removed study-specific parent trial numbers in the 
eligibility criteria for optional tolvaptan treatment 
to generalize the enrollment criteria from previous 
tolvaptan pediatric trials for hyponatremia.
To generalize trial entry criteria.
Synopsis, Section 2 (Trial Rationale and 
Objectives), Section 2.3 (Trial Objectives), Section 
3.1.1 (Core Safety Follow-up Component), Section 
3.3.1 (Core Safety Follow-up Component), Section 
3.4.1 ((Informed Consent/Assent), Section 3.4.2 
(Inclusion Criteria), Section 3.7.1 (Core Safety 
Follow-up Component), Table 3.7.1-1 (Core Safety 
Follow-up Component - Schedule of Assessments
for All Subjects), Section 3.7.2 (Optional Tolvaptan 
Treatment Component), Section 3.7.3.1.1 
(Baseline), Section 3.10 (Definition of Completed 
Subjects), Section 7.1 (Sample Size)
Added percentage of subjects who have recurrence 
of hyponatremia while on tolvaptan as a secondary 
efficacy endpoint
To align with Pediatric Investigational Plan 
requirements.
Synopsis, Section 3.5.2.1
Reduced the sample size from approximately 140 to 
approximately 100 male or female subjects.
EMA required safety follow-up data for at least 100 
subjects. 
Synopsis, Section 3.3.1 (Core Safety Follow-up 
Component), Section 7.1 (Sample Size) 
Removed Tanner Staging analysis method
Tanner Staging will not be analyzed using the 
Cochran-Mantel-Haenszel row mean scores differ 
test controlling for subjects.
Synopsis, Section 7.4.2
Updated protocol with trial data, exposure, and 
references from IB edition 21.
Updated with current information on Health Canada 
and EMA approvals for tolvaptan in ADPKD, on 
updated tolvaptan exposure and reference 
information.
Section 1 (Introduction)
Updated safety outcome variables applicable in 
core safety component to indicate that they apply to 
all subjects.
All subjects participating in this trial will be 
evaluated for safety, as the optional tolvaptan 
treatment component is a subgroup of the core 
safety component.  It was preferred not to 
differentiate this component. 
Section 3.5 (Outcome Variables), Section 7.4 
(Primary and Secondary Outcome Analysis)
Removed exploratory outcomes related to 
neurocognitive battery assessments.
There was no requirement in the Pediatric 
Investigational Plan to conduct neurocognitive 
assessments.  They were therefore removed.
Section 3.5.3 (Exploratory Variables), Section 7.4.3 
(Exploratory Outcome Analyses) 


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Description of Change
Rationale for Change
Sections Affected by Change
Replaced trial tolvaptan references to IMP, where 
applicable.
In Amendment #2, there were references to 
tolvaptan rather than IMP.  However, to 
differentiate between commercial use of tolvaptan, 
IMP will be referenced in this trial.
Throughout protocol.
Updated adverse events reporting protocol 
language.
AE wording revised to match current protocol 
template language
Section 5.1 (Definitions)
Updated SAE reporting guidelines related to 
hospitalization.
SAE wording revised to match current protocol 
template language
Section 5.1 (Definitions)
Updated IRE reporting guidelines related to 
potential drug induced liver injury cases.
The protocol template has been updated to no 
longer isolate Hy’s Law cases for IRE reporting.  
Potential DILIs must be reported as an IRE.
Section 5.4 (Potential Drug-induced Liver Injury)
Updated Trial Design Schematic
To align with changes made to the Schedule of 
Assessments.
Figure 3.1-1
Core Safety Follow-up Component Changes
Modified the requirements for in-clinic visits vs. 
telephone assessments for each of the visits in the 6 
month core safety component.
To reduce subject burden, several of the clinic visits 
were replaced by telephone visits. Subsequently, 
in-clinic visits were removed from the Month 2 and 
Month 4 visits.
Synopsis, Figure 3.1-1 (Trial Design Schematic), 
Section 3.1.1 (Core Safety Follow-up Component), 
Section 3.7.1 (Core Safety Follow-up Component), 
Table 3.7.1-1 (Core Safety Follow-up Component -
Schedule of Asessments for All Subjects), Section 
3.7.3.1 (Core Safety Follow-up Component)
Clarified which assessments and time points from 
the previous tolvaptan trial will serve as baseline 
assessments.
To reduce subject burden, assessment data could be 
applied from the previous trial if they were 
performed within 30 days of baseline. 
Section 3.1.1 (Core Safety Follow-up Component), 
Section 3.7.1 (Core Safety Follow-up Component), 
Table 3.7.1-1 (Core Safety Follow-up Component -
Schedule of Assessments for All Subjects), Section 
3.7.3.1.1 (Baseline)
Clarified that subjects who do not enroll directly 
from the parent trial into Trial 156-11-294 will still 
be eligible to enroll.
Amendment 2 was not clear about whether there 
could be a lapse between the parent trial and 
enrollment into this trial.  Further clarification was 
provided that allowed a lapse to occur. 
Synopsis, Section 3.1.1 (Core Safety Follow-up 
Component), Section 3.7.1 (Core Safety Follow-up 
Component)
Clarified requirements for a full versus directed
physical examination and neurological 
examination.  Added a fontanelle assessment as age 
appropriate.
To reduce subject burden while evaluating 
examination requirements with any lapse between 
the previous tolvaptan trial.
Table 3.7.1-1 (Core Safety Follow-up Component -
Schedule of Assessments), Section 3.7.3.1.1 
(Baseline), Section 3.7.3.1.3 (Month 6/Early 
Termination), Section 3.7.5.4 (Physical 
Examination and Vital Sign Assessments)


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Description of Change
Rationale for Change
Sections Affected by Change
Removed Neurocognitive Assessments.
There was no requirement in the Pediatric 
Investigational Plan to conduct neurocognitive 
assessments so they were deleted from the protocol.
Table 3.7.1-1 (Core Safety Follow-up Component:  
Schedule of Assessments for All Subjects), Section 
3.7.3.1.1 (Baseline), Section 3.7.3.1.3 (Months 2, 4 
and 6/Early Termination), Section 3.7.7 
(Exploratory Assessments).
Clarified timepoint to obtain consent and assent 
prior to conducting trial-level procedures.
In amendment 2, allowance was given to obtain the 
ICF/assent in the parent trial in advance of the 
rollover trial participation.  Given that the 
ICF/assent is a baseline assessment, it is more 
appropriate to obtain it at this timepoint.
Section 3.4.1 (Informed Consent/Assent)
Summarized required laboratory tests in Table 
3.7.5.2-1.
For ease of site use, this was added to the protocol.
Table 3.7.5.2-1.  
Removed collection of serum sodium as a safety 
variable in the core safety follow-up population.
To reduce subject burden.
Synopsis, Section 3.5.2.2 (Safety Variables), Table 
3.7.1-1 (Core Safety Follow-up Component -
Schedule of Assessments for All Subjects), Section 
7.4.2 (Secondary Outcome Variables)
Clarified liver function test collection requirements 
at baseline, Month 1 and Month 2.
For ease of site use, this was clarified in the 
protocol.
Figure 3.1-1 (Trial Design Schematic), Section 
3.1.1 (Core Safety Follow-up Component), Section 
3.7.1 (Core Safety Follow-up Component), Section 
3.7.5 (Safety Assessments)
Added vital status assessment at Month 6 for 
subjects who discontinue the trial but consent to 
continued telephone contact.
To make every attempt to verify safety of patients 
who participate in this protocol throughout the 
duration of their expected participation at 6 months
Section 3.7.1-1 (Core Safety Follow-up Component 
- Schedule of Assessments for All Subjects), 
Section 3.7.3 (Schedule of Assessments), Section 
3.7.3.1.3 (Month 6/Early Termination)
Remove hyponatremia history at Month 6.
Not applicable.
Table 3.7.1-1, Section 3.7.3.1.3.
Optional Tolvaptan Treatment Component Changes
Limited optional tolvaptan treatment up to a 
maximum of 6 months participation in the core 
safety component.  
In amendment 2, the optional treatment was 
indefinate.  The protocol has been updated to 
provide a finite timepoint, the duration not to 
exceed the core safety Month 6 visit.
Synopsis, Section 2.1.2 (Optional Tolvaptan 
Treatment Component), Section 3.1.2 (Optional
Tolvaptan Treatment Component)
Updated eligibility criteria of optional tolvaptan 
treatment #1.
Due to unavailability of an age appropriate 
formulation, the entrance criteria for the lower age 
groups is being modified to allow subjects ≥4 years 
of age (or per local Health Authority age 
restrictions) and ≥10 kg. 
Appendix 5, Section 3.2.1.2.


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Amendment 3 9 Nov 2015
Description of Change
Rationale for Change
Sections Affected by Change
Updated eligibility criteria of optional tolvaptan 
treatment #2
Clarify that the clinical need for optional tolvaptan 
dosing is not contingent for general trial enrollment.
Appendix 5
Updated eligibility criteria of optional tolvaptan 
treatment #4.
Modification made for ability to swallow tablets 
due to unavailability of an age appropriate 
formulation.
Appendix 5
Updated ineligibility criteria for tolvaptan treatment 
#17.
Removed IRE form completion requirement due to 
change in IRE definition.
Appendic 5
Updated ineligibility criteria for tolvaptan treatment 
#18.
Clarified entry requirement related to cirrhosis.
Appendix 5
Updated ineligibility criteria for tolvaptan treatment 
#24.
Removed specific drug trial numbers to make more 
general.
Appendix 5
Updated ineligibility criteria for tolvaptan treatment 
#25.
Due to unavailability of an age appropriate 
formulation, the ineligibility criteria was modified 
to exclude subjects < 4 years of age (or per local 
Health Authority age restrictions), weight < 10 kg 
and who are unable to swallow tablets.
Appendix 5
Specified that the optional tolvaptan treatment 
component objective duration is up to 6 months.
In amendment 2, the optional treatment was 
indefinate.  The protocol has been updated to 
provide a finite timepoint, the duration not to 
exceed the core safety Month 6 visit.
Synopsis, Section 2.3 (Trial Objectives)
Provided guidelines regarding how to proceed with 
the treatment interruption period on Days 31 – 34.
In amendment 2, the optional tolvaptan treatment 
dosing interruption period, days 31-32 included - 1 
day visit window.  However, many logistical 
questions were raised, particularly with the IWRS
and the mandatory requirement to reinitiate 
treatment after 72 hours off treatment.  Therefore, 
in this amendment, the visit windows were removed 
during the interruption period.
Figure 3.1-1 (Trial Design Schematic), Table 3.7.2-
1 (Schedule of Assessments for Each Treatment 
Cycle), Section 3.7.3.2 (Optional Tolvaptan 
Treatment Component)
Clarified that a new treatment cycle is required if a 
subject is off tolvaptan treatment for ≥ 72 hours.
In this amendment, subjects who have been off 
tolvaptan for ≥ 72 hours are required to retitrate in a 
hospital setting, rather than > 72 hours as in the 
previous version.
Synopsis, Section 3.1.2 (Optional Tolvaptan 
Treatment Component), Section 3.2.1 (Optional 
Tolvaptan Treatment Component), Table 3.7.2-1 
(Schedule of Assessments for Each Treatment 
Cycle), Section 3.7.3.2.4.3 (Day 33) 


Protocol 156-11-294
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282
Amendment 3 9 Nov 2015
Description of Change
Rationale for Change
Sections Affected by Change
Removed Table 3.2.2-1.
To streamline the dosing section, the table was 
removed since this information was provided 
elsewhere in the protocol.
Table 3.2.2-1
Added trial day numbers associated with Month 2+ 
visits to further clarify time point data collection.
The trial day numbers are clarified in Sections 
3.7.3.2.5 and 3.7.3.2.6, and in the Schedule of 
Assessments.
Section 3.7.3.2.5 (Treatment Cycle Month 2), 
Section 3.7.3.2.6 (Maintenance Phase), Table 3.7.2-
1 (Schedule of Assessments for Each Treatment 
Cycle)
Clarified urine vs. serum pregnancy test 
requirements.
In amendment 2, there was no clear specification of 
whether the pregnancy test would be assessed from 
urine or serum.  This is clarified in the Schedule of 
Assessments and Section 5.5 that the investigator 
can chose either one, as long as a serum pregnancy 
test is done if the urine pregnancy is positive.
Section 5.5 (Pregnancy), Table 3.7.2-1 (Schedule of 
Assessments for Each Treatment Cycle)
Added serum creatinine assessment as a safety 
variable
Additional safety monitoring of the subjects
Section 3.5.2.2 (Safety Variables), Table 3.7.2-1 
(Schedule of Assessments for Each Treatment 
Cycle), Section 3.7.3.2.1 (Pretreatment Baseline 
Visit), Section 3.7.3.2.4 (Day 30 Interruption (± 1) 
Days Post-first Dose, Section 3.7.3.2.5 (Treatment 
Cycle Month), Section 3.7.3.2.6.1 (Treatment Cycle 
Month 3), Section 3.7.3.2.7.1 (First Follow-up:  24 
(± 4) hours Post last Dose) , Table 3.7.5.3-1 
(Clinical Laboratory Tests During Optional 
Tolvaptan Treatment), Section 7.4.2 (Secondary 
Outcome Measures). 
Clarified that initial dosing should be given and all 
titrations should occur in a hospital setting.
Additional wording was added to clarify these 
requirements.
Synopsis, Section 3.1.2.1 (Treatment Interruption 
on Day 30), Section 3.2.1.2 (Titration Guidelines 
for the Optional Tolvlaptan Treatment Component)
Added table for serum sodium assessments for 
efficacy and safety (supplemental)
For ease of site use, this was added to the protocol.
Table 3.7.4.1.2-1 (Serum Sodium Assessments 
During the Optional Tolvaptan Component)
Clarified requirements for a full versus directed 
physical examination and neurological 
examination. Added a fontanelle assessment as age 
appropriate. 
Provide further clarity to the examination 
requirements during the treatment cycle and giving 
the investigator the option to complete a 
neurological examination if there are any positive 
findings on the clinical status assessment.
Table 3.7.2-1, Section 3.7.3, and 3.7.5.4, Section 
3.7.5.5


Protocol 156-11-294
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283
Amendment 3 9 Nov 2015
ADDITIONAL RISK TO THE SUBJECT: There is no additional risk to the subjects
A complete redline version of this amendment showing all changes from the previous version will be produced and available upon 
final approval of this amendment.


Protocol 156-11-294
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Amendment 3 9 Nov 2015
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal, and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities.  I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, tolvaptan, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general.  I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) or receive a 
favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in the 
clinical trial facility where tolvaptan will be tested prior to commencement of this trial.  I agree to 
adhere strictly to the attached protocol (unless amended in the manner set forth in the sponsor's 
Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor.  I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable.  I agree to allow sponsor monitors and auditors full access 
to all medical records at the research facility for subjects screened or enrolled in the trial.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines.  I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s).  I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s).  I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date


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OPC-41061
Protocol 156-11-294 Amendment 3
0000835721
8.0
Clinical Pharmacology
10-Nov-2015 14:24 GMT+00
Clinical Approval
10-Nov-2015 16:10 GMT+00
Biostatistics Approval
10-Nov-2015 16:33 GMT+00
PPD

SAP_001.pdf: 
Protocol 156-11-294 
Confidential - Proprietary Information 
Protocol number: 156-11-294
Document title: A Phase 3b, Multicenter, Extension Follow-up Trial 
to Evaluate the Long-term Safety of Children and Adolescent 
Subjects With Euvolemic or Hypervolemic Hyponatremia Who 
Have Previously Participated in a Trial of Titrated Oral SAMSCA 
(Tolvaptan)
Version number: 2.0
Date of the document: 19 October 2017
NCT number:    NCT02020278


Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational New Drug 
OPC-41061
A Phase 3b, Multicenter, Extension Follow-up Trial to Evaluate the Long-term Safety of 
Children and Adolescent Subjects with Euvolemic or Hypervolemic Hyponatremia Who 
Have Previously Participated in a Trial of Titrated Oral SAMSCA(Tolvaptan)
Protocol No. 156-11-294
IND No. 54,200
NDA No. 22-275
EudraCT No. 2013-002810-11
Statistical Analysis Plan
Date: 19 Oct 2017
Protocol: 31 Oct 2013
Protocol Amendment 1: 05 Sep 2014
Protocol Amendment 2: 26 Feb 2015
Protocol Amendment 3: 09 Nov 2015
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.


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Table of Contents
Table of Contents...........................................................................................2
1
Introduction ..........................................................................................3
2
Trial Objective......................................................................................3
3
Trial Design...........................................................................................3
4
Sample Size and Power Justification..................................................5
5
Statistical Methods ...............................................................................6
5.1
Efficacy Analysis ................................................................................................6
5.1.1
Data Sets Analyzed...........................................................................................6
5.1.2
Handling of Missing Data.................................................................................6
5.1.3
Baseline Characteristics and Baseline Comparability......................................6
5.1.4
Treatment Compliance......................................................................................7
5.1.5
Protocol Deviations ..........................................................................................7
5.1.6
Primary Outcome Analyses ..............................................................................7
5.1.6.1
Analysis of Primary Outcome Endpoint .......................................................7
5.1.6.2
Technical Computational Details for Primary Outcome Analysis................7
5.1.7
Secondary Outcome Analysis...........................................................................7
5.1.7.1
Analyses of Secondary Outcome Variables..................................................7
5.1.7.2
Technical Computational Details for the Analysis of the Secondary 
Endpoints ......................................................................................................8
5.2
Safety Analysis....................................................................................................9
5.2.1
Duration of Exposure to Trial Medication......................................................10
5.2.2
Adverse Events ...............................................................................................10
5.2.3
Laboratory Test Results..................................................................................11
5.2.4
Vital Signs Data..............................................................................................11
5.2.5
Electrocardiogram Data..................................................................................11
5.2.6
Post-baseline Concomitant Medications.........................................................11
6
SAP References...................................................................................12


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1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for statistical analysis and reporting of
efficacy and safety data of Trial 156-11-294. All amendments to the protocol are taken 
into consideration in developing this SAP.
2
Trial Objective
The objective of this trial is to provide 6 months of safety follow-up for children and 
adolescents with dilutional (euvolemic or hypervolemic) hyponatremia who have 
previously participated in a tolvaptan hyponatremia trial, and to assess the efficacy of 
tolvaptan in increasing serum sodium for those subjects who receive optional continuing 
tolvaptan treatment of variable duration (up to 6 months).
Core Safety Follow-up Component

For all subjects:  To evaluate the post-treatment safety follow-up of children and 
adolescent subjects with dilutional (euvolemic or hypervolemic) hyponatremia who 
have previously participated in a tolvaptan hyponatremia trial.
Optional Tolvaptan Treatment Component

For subjects who receive optional tolvaptan treatment:  To demonstrate that tolvaptan 
safely and effectively achieves and maintains increased serum sodium concentrations 
in children and adolescent subjects with dilutional (euvolemic or hypervolemic)
hyponatremia when used for both multiple short-term treatments, and/or longer 
chronic treatments.
3
Trial Design
This trial consists of 2 components, a 6-month safety follow-up trial, and an embedded 
optional tolvaptan treatment trial for eligible subjects.  
Core Safety Follow-up Component
The core safety follow-up component of the trial is a 6-month period in which pediatric 
subjects (children and adolescents) with dilutional (euvolemic or hypervolemic) 
hyponatremia who previously participated in a tolvaptan hyponatremia trial will be 
followed (at a clinical trial site and/or through telephone calls), regardless of the need for 
treatment for hyponatremia, to assess the long-term safety of tolvaptan. There is no 
screening phase.  


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Enrollment into this trial should follow completion or discontinuation from the previous 
tolvaptan hyponatremia trial; the subject must have been off investigational medicinal 
product (IMP) for at least 7 days between trials.  A longer lapse between completion of 
the previous tolvaptan hyponatremia trial and enrollment into this trial is permitted while 
enrollment is open.
The final laboratory assessments for liver function tests (LFTs) from the previous 
tolvaptan trial can serve as the baseline laboratory assessments for this trial if the values 
are within the normal range, and collected within 30 days of the baseline visit for this 
trial.  However, LFTs for these subjects will be collected at Month 1 or Month 2 at a 
clinical site visit or local laboratory.  If LFTs from the previous tolvaptan trial are 
abnormal, or collected > 30 days of the baseline visit of this trial, they will be assessed at 
baseline.  
The last assessments in the previous tolvaptan trial will serve as the baseline assessments 
if collected within 30 days of enrollment into this trial.  Otherwise, assessments will be 
repeated if > 30 days have lapsed since the previous tolvaptan trial. 
Subjects enrolled in this trial will be assessed up to 7 times over the 6-month core safety 
follow-up component of the trial.  The baseline and the Month 6/Early Termination (ET) 
visits are performed in the clinic, while assessments during Months 1, 2, 3, 4 and 5 will 
be conducted by telephone, unless LFTs are required at Month 1 or Month 2.  During the 
in-clinic visits, subjects are evaluated for relevant trial information.  
Baseline Visit
All subjects will attend the clinic for the baseline visit.
Months 1, 2, 3, 4 and 5
All subjects will receive telephone assessments for Months 1, 2, 3, 4, and 5.  If LFTs are 
required at Month 1 or Month 2, the subject may obtain these results through a clinic visit 
or from a local laboratory. 
Month 6/End of Trial Visit
All subjects will attend the clinic for the Month 6/End of Trial visit.
Optional Tolvaptan Treatment Component
Subjects enrolled in the 6-month core safety follow-up component may be eligible to 
receive optional tolvaptan treatment for their hyponatremia. Eligibility for optional 
tolvaptan treatment must be determined at the pre-treatment baseline visit (Day −4 to Day 
1) of each dosing cycle.  Eligible subjects can be treated at any time with optional 


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tolvaptan during the 6-month core safety follow-up component.  Optional tolvaptan 
treatment duration will be case-specific; it can be short-term or long-term, and consist of 
1 or more treatment cycles.  When a cycle with optional tolvaptan treatment is completed, 
including the Follow-up Phase visits, subjects will continue in the core safety component 
to complete the remainder of visits until Month 6.  Within this trial, tolvaptan treatment 
will not extend beyond the 6-month core safety trial period.  If the subject completes the 
6-month core safety component while on optional tolvaptan treatment, the subject will 
complete the Month 6 core safety component visit, terminate treatment, and immediately 
enter the Follow-up Phase. 
If a subject simultaneously participates in both core safety and optional tolvaptan 
treatment components, the visit days will be calculated between both components to 
ensure the assessments can be overlapped, where applicable.
Thirty days after the start of optional tolvaptan treatment, subjects will interrupt treatment 
for up to 2 doses (Days 31-32).  The need for continuing treatment after this tolvaptan 
interruption will be assessed at minimum once daily (or more as needed) during this time. 
Subjects who are expected to receive tolvaptan for greater than 30 days duration should 
demonstrate the need for continued treatment by discontinuing tolvaptan for up to 2 
consecutive doses while undergoing close monitoring of serum sodium levels.
However, there is a subgroup of subjects who have an identifiable cause for 
hyponatremia that has not (or cannot be) changed that will have an option to be excused 
from this brief interruption of tolvaptan.  Examples of such causes include concomitant 
treatment for refractory seizures with a hyponatremia-inducing medication such as 
oxcarbazepine (which can increase vasopressin production by the pituitary) that cannot 
be changed or discontinued, or subjects with a known underlying hyponatremia inducing 
condition such as volume overload from a failing Fontan repair.
The optional tolvaptan treatment component of the trial will be available for the 6-month 
duration of the core safety component for each subject. 
4
Sample Size and Power Justification
Sample size was not determined by a formal computation to achieve a target power.  It is 
expected that approximately 100 subjects may enroll from previous tolvaptan pediatric 
trials for hyponatremia 


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5
Statistical Methods
5.1
Efficacy Analysis
Due to the early termination status, not all planned analyses will be provided due to lack 
of data. For an example, no subject received optional Tolvaptan treatment, the efficacy
analyses specified in the SAP will not be applied to Optional Tolvaptan Treatment 
Component. 
5.1.1
Data Sets Analyzed
The following datasets are defined for this trial:

Enrolled Subjects (core safety follow-up component)

Core Dataset:  comprises all subjects for whom an ICF is signed for 
the trial.

Treated Subjects (optional tolvaptan treatment component)

Safety Dataset:  comprises those subjects who receive at least one dose 
of tolvaptan.

Efficacy Dataset:  comprises those subjects in the safety dataset who 
have at least one post-baseline efficacy evaluation for serum sodium 
concentration.
5.1.2
Handling of Missing Data
The primary dataset for efficacy analyses will be the observed cases (OC) dataset.  The 
OC dataset will consist of the actual observations recorded at each visit so that no 
imputation of missing values will be made.
5.1.3
Baseline Characteristics and Baseline Comparability
Demographic characteristics and medical history at baseline will be summarized by 
descriptive statistics, e.g., proportion, mean, median, standard deviation(SD), minimum
and maximum values.
Baseline characteristics by age categories (≥ 4 weeks to < 4 years, ≥ 4 years to < 8 years, 
≥ 8 years to < 12 years, ≥ 12 years to < 18 years) will also be provided. Baseline 
characteristics by underlying etiology (heart failure, hepatocellular disease, syndrome of 
inappropriate antidiuretic hormone secretion (SIADH) or other diseases) will be provided
as well.


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5.1.4
Treatment Compliance
For subjects participating in the Optional Tolvaptan Treatment Component, treatment 
compliance will be calculated for each cycle by dividing the total dosage taken during the 
cycle by the total dosage the subjects are scheduled to take during the cycle based on the 
Study Medication panel of the case report form (CRF). The overall treatment compliance 
across cycles will be provided 
5.1.5
Protocol Deviations
Protocol deviations data will be summarized by type of deviations (e.g., deviations in 
entry criteria, dosing, concomitant medication, procedural, etc.) by center and treatment 
group. In addition, a subject listing will be provided describing the deviations for each 
subject.
5.1.6
Primary Outcome Analyses
5.1.6.1
Analysis of Primary Outcome Endpoint
The primary endpoint for all subjects participating in the Optional Tolvaptan Treatment 
Component of the trial is change from baseline in serum sodium while tolvaptan is being 
administered. The descriptive statistics will be provided for the primary endpoint.
The primary endpoint will be analyzed by age groups (≥ 4 weeks to < 4 years, ≥ 4 years 
to < 8 years, ≥ 8 years to < 12 years, ≥ 12 years to < 18 years).
5.1.6.2
Technical Computational Details for Primary Outcome Analysis
1) Baseline for the primary endpoint is the last evaluation of serum sodium prior to the 
first dose at each cycle in the Optional Tolvaptan Treatment Component.
2) For safety purpose, additional unscheduled serum sodium between scheduled 
efficacy endpoints may be collected measured in the local hospital labs. These 
assessments of serum sodium will not be included in the primary efficacy analysis.
3) The primary analysis will be only performed on the Optional Treatment Efficacy 
Sample.
5.1.7
Secondary Outcome Analysis
5.1.7.1
Analyses of Secondary Outcome Variables
The secondary endpoints for all subjects receiving tolvaptan in the Optional Tolvaptan 
Treatment Component of the trial include the following:

Percentage of subjects who require rescue therapy while on tolvaptan

Percentage of subjects who have recurrence of hyponatremia while on tolvaptan


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
Percentage of subjects requiring continuation of tolvaptan following 30 days of 
treatment

Percentage of subjects with overly rapid correction in serum sodium (12 mEq/L 
[mmol/L]) in 24 hours after the first dose at introduction or reintroduction of 
tolvaptan

Changes from baseline in ALT, AST, BT and creatinine for subjects on tolvaptan
The secondary endpoints for subjects participating in the Core Safety Follow-up 
Component of the trial include:

Frequency of AE reports

Change from baseline in QoL assessments

Change from baseline in growth percentiles by visit for body height and weight

Tanner Staging progression score (at 6 months)
All secondary endpoints will be summarized using descriptive statistics.
5.1.7.2
Technical Computational Details for the Analysis of the 
Secondary Endpoints
1) Baseline for the continuous secondary endpoints of the subjects receiving tolvaptan 
in the Optional Tolvaptan Treatment Component is the last evaluation prior to the 
first dose at each cycle in the Optional Tolvaptan Treatment Component. This 
applies to ALT, AST and BT.
2)
Baseline for the continuous secondary endpoints except QoL and serum sodium of 
the subjects participating in the Core Safety Follow-up Component is the last
evaluations from the previous trial , if the last evaluation was done in previous trials
within one month of this trial starts. If more than one month passes between trials, 
the baseline will be the evaluations at the baseline visit of this trial.
The baseline for QoL and serum sodium of the subjects in the Core Safety Follow-up 
Component is the evaluations at the baseline visit.
3) The QoL assessment includes the PedsQL Generic Core Scale (QoL GCS) and 
PedsQL Multidimensional Fatigue Scale (QoL MFS).  For the QoL GCS, the change 
from baseline in QoL GCS total score, physical health summary score, and 
psychosocial health summary score will be analyzed using the descriptive statistics.  
For the QoL MFS, the QoL MFS total score will be analyzed using the descriptive 
statistics.
4) The QoL GCS scale consists of 23 items encompassing physical, emotional, social, 
and school domains. 
For ease of interpretability, items are reversed scored and linearly transformed to a 
0-100 scale, so that higher scores indicate better HRQOL (Health-Related Quality of 
Life). 


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To reverse score, transform the 0-4 scale items to 0-100 as follows:  0 = 100, 1 = 75, 
2 = 50, 3 = 25, 4 = 0.
To create scale scores, the mean is computed as the sum of the items divided by the 
number of items answered (this accounts for missing data). If more than 50% of the 
items in the scale are missing, the scale scores should not be computed. If 50% or 
more items are completed, then impute missing scores by the mean of the completed 
items in a scale.
To create the Psychosocial Health Summary Score, the mean is computed as the sum 
of the items divided by the number of items answered in the Emotional, Social, and 
School Functioning Scales. The Physical Health Summary Score is the same as the 
Physical Functioning Scale Score.
To create the total scale score, the mean is computed as the sum of all the items 
divided by the number of items answered on all the scales.
Child self-reported data for subjects with age 5 years will be used in the analysis, 
while for subjects with age < 4 years, parent-reported data will be used.
5) The QoL MFS scale consists of 18 items in 3 subscales:  general fatigue, sleep/rest 
fatigue, and cognitive fatigue. 
Items are reversed scored and linearly transformed to a 0-100 scale as follows: 
0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0.
To create scale scores for each dimension, the mean is computed as the sum of the 
items divided by the number of items answered.
The total QoL MFS score will be calculated by summing up all the items divided by 
the number of items answered on all the scales.
If more than 50% of the items in the scale are missing, the scale scores should not be 
computed.  If 50% or more items are completed, then impute missing scores by the 
mean of the completed items in a scale.
Child self-reported data for subjects with age 5 years will be used in the analysis, 
while for subjects with age < 4 years, parent-reported data will be used. 
5.2
Safety Analysis
Due to the early termination status, not all planned safety analyses will be provided due 
to lack of data. For an example, no subject received optional Tolvaptan treatment, the 
safety analyses specified in the SAP will not be applied to Optional Tolvaptan Treatment 
Component.
Safety variables to be analyzed include adverse events (AEs), clinical laboratory data, 
and vital signs.  In general, summary statistics will be provided for safety variables based 
on all available data.


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Baseline of the subjects receiving tolvaptan in the Optional Tolvaptan Treatment 
Component is the last evaluation prior to the first dose at each cycle in the Optional 
Tolvaptan Treatment Component.  Baseline of the subjects participating in the Core 
Safety Follow-up Component is the last evaluations from the previous trial (tolvaptan in 
Trial 156-08-276), if the last evaluation was done in previous trials within one month of 
this trial starts.  If more than one month passes between trials, the baseline will be the 
evaluations at the baseline visit of this trial.
Safety analyses by age categories (≥ 4 weeks to < 4 years, ≥ 4 years to < 8 years, ≥ 8 
years to < 12 years, ≥ 12 years to < 18 years) will be provided. Safety analysis by 
underlying etiology (heart failure, hepatocellular disease, SIADH/other) will also be
provided.
5.2.1
Duration of Exposure to Trial Medication
Duration of exposure to each treatment of each subject will be summarized for subjects
who enrolled in Optional Tolvaptan Treatment Component.  A subject’s duration of 
exposure is defined as the trial medication end date - trial medication start date + 1.    
5.2.2
Adverse Events
Definitions: 

A treatment-emergent adverse event (TEAE) is an event that is observed or reported 
after administration of trial medication in this trial that was not present prior to trial
medication administration or an event that represents the exacerbation of a 
pre-existing event.  Exacerbation includes any event that increases in frequency or 
severity or becomes classified as serious after the start of treatment in this trial.  

An adverse withdrawal is a subject who withdrew from the trial due to an AE.

A serious adverse event (SAE) is an AE that is classified as serious according to the 
criteria specified in the trial protocol.
The incidence of the following events will be summarized:
AEs and TEAEs
AEs and TEAEs by severity
TEAEs potentially causally related to the IMP
AEs and TEAEs with an outcome of death
Serious AEs and TEAEs
AEs and TEAEs leading to discontinuation
All AEs will be coded by MedDRA (Medical Dictionary for Regulatory Activities) 
system organ class and preferred term.


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5.2.3
Laboratory Test Results
Summary statistics for the clinical laboratory measurements at baseline and post-baseline 
visits, and summary statistics of changes from baseline to each visit will be presented.
Shift tables will be produced, assessing low-normal-high (at baseline) to low-normal-high 
(at post-baseline visit). 
The incidence of potentially clinically significant abnormal lab results will also be 
summarized.  Listings of potentially clinically significant abnormalities will also be 
provided.
According to FDA (Food and Drug Administration) Guidance,1 laboratory measurements 
that signal the potential for drug-induced liver injury (DILI) will be reported.  An 
incidence table and a listing will be provided for subjects who meet one or combinations 
of the following criteria: 
1) ALT (alanine transaminase) or AST (aspartate transaminase) 3x upper limit of 
normal (ULN) (or baseline value for subjects with abnormal baseline)
2) Increase in bilirubin 2x ULN (or baseline value for subjects with abnormal 
baseline)
5.2.4
Vital Signs Data
Descriptive statistics will be provided for both vital signs and change from baseline in 
vital signs. The incidence of potentially clinically significant vital sign results will also 
be summarized. Listings of potentially clinically significant abnormalities will also be 
provided. 
For a subject with repeat measures in either vital signs or lab tests at a visit, the last
repeat will be used in the by visit summary.  However, for outlier analysis (such as 
clinically significant abnormalities), data from all visits, no matter they are from the 
original visits, repeats, or unscheduled visits, will be included.
5.2.5
Electrocardiogram Data
Electrocardiogram (ECG) data will not be summarized since there are no trial mandated 
ECGs.
5.2.6
Post-baseline Concomitant Medications
Concomitant medications used post-baseline will be summarized in two categories of 
time interval:  during the trial medication period and after the trial medication period. In 
each case, the use of concomitant medications will be summarized by number and 
percentage of users.


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6
SAP References 
1
Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
US Department of Health and Human Services, Food and Drug Administration, and 
Center for Drug Evaluation and Research (CDER), July 2009.


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Meaning of Signature
Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
OPC-41061
SAP1561129414
0001163416
2.0
Clinical Approval
23-Oct-2017 16:23 GMT+00
Biostatistics Approval
23-Oct-2017 21:09 GMT+00
PPD