Conditions: Hyponatremia
Keywords: Hyponatremia Euvolemic Hypervolemic Serum sodium Dilutional hyponatremia Electrolyte abnormality Electrolyte imbalance Metabolic disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
The purpose of this trial was to demonstrate that tolvaptan effectively and safely increases and maintains serum sodium concentrations in children and adolescent participants with euvolemic or hypervolemic hyponatremia.

Detailed description:

Arms:
arm 1: All participants initially received tolvaptan once daily for the first 2 days. A third day of treatment was permitted if a participant had not reached the desired sodium target improvement per the investigator's judgment.

At the end of Day 2 (or Day 3), responders (participants who achieved an increase in serum sodium by ≥4 millimoles/liter \[mmol/L\]) were randomized to either the Early or Late Withdrawal Group. Non-responders could continue treatment with tolvaptan for an additional 2 days.

Discontinued tolvaptan treatment immediately after randomization.

All participants were observed up to 14 days post randomization. arm 2: All participants initially received tolvaptan once daily for the first 2 days. A third day of treatment was permitted if a participant had not reached the desired sodium target improvement per the investigator's judgment.

At the end of Day 2 (or Day 3), responders (participants who achieved an increase in serum sodium by ≥4 mmol/L) were randomized to either the Early or Late Withdrawal Group in Treatment Phase B. Non-responders could continue treatment with tolvaptan for an additional 2 days.

Continued treatment for 2 additional days.

All participants were observed up to 14 days post randomization.

Interventions: intervention 1: Tolvaptan
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Protocol: 156-08-276 
Confidential - Proprietary Information 
 Protocol number: 156-08-276. 
 Document title: A Phase 3b, Multicenter, Open-label, Randomized 
Withdrawal Trial of the Effects of Titrated Oral SAMSCA® (Tolvaptan) on 
Serum Sodium, Pharmacokinetics, and Safety in Children and Adolescent 
Subjects Hospitalized With Euvolemic or Hypervolemic Hyponatremia 
 Version number: Amendment 5. 
 Date of the document: 17 Nov 2015. 
 EudraCT number: 2013-002005-59. 


Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
SAMSCA, Tolvaptan (OPC-41061)
REVISED CLINICAL PROTOCOL
A Phase 3b, Multicenter, Open-label, Randomized Withdrawal Trial of the Effects of 
Titrated Oral SAMSCA(Tolvaptan) on Serum Sodium, Pharmacokinetics, and Safety in 
Children and Adolescent Subjects Hospitalized With Euvolemic or Hypervolemic 
Hyponatremia
Protocol No. 156-08-276
IND No. 54,200
NDA No. 22-275
EudraCT No. 2013-002005-59
CONFIDENTIAL – PROPRIETARY INFORMATION
Drug Development Phase:
3b
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States
Sponsor Representatives:
Phone 
; Fax 
E-mail:  
Phone 
; Fax 
E-mail:  
Immediately Reportable Event:
INC Research (see Appendix 1)
Issue Date:
03 Jul 2013
Date of Amendment 1:
04 Nov 2013
Date of Amendment 2:
19 May 2014
Date of Amendment 3:
26 February 2015
Date of Amendment 4:
07 May 2015
Date of Amendment 5:
17 Nov 2015


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Protocol Synopsis
Name of Company:  Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Product:  SAMSCA, Tolvaptan 
(OPC-41061)
Protocol No. 156-08-276
IND No. 54,200
NDA No. 22-275
EudraCT No. 2013-002005-59
Protocol Title:
A Phase 3b, Multicenter, Open-label, Randomized Withdrawal 
Trial of the Effects of Titrated Oral SAMSCA(Tolvaptan) on 
Serum Sodium, Pharmacokinetics, and Safety in Children and 
Adolescent Subjects Hospitalized With Euvolemic or 
Hypervolemic Hyponatremia
Clinical Phase/Trial 
Type:
Phase 3b, therapeutic confirmatory
Treatment 
Indication:
Euvolemic or hypervolemic hyponatremia
Objectives:
Primary Objective:
To demonstrate that tolvaptan effectively and safely increases 
and maintains serum sodium concentrations in children and 
adolescent subjects with euvolemic or hypervolemic 
hyponatremia.
Secondary Objective:
To assess tolvaptan’s pharmacokinetics (PK) and its effect on 
fluid balance in children and adolescent subjects with 
euvolemic or hypervolemic hyponatremia.
Trial Design:
This is an open-label, multicenter, multiple-dose, randomized 
withdrawal, parallel-group trial of tolvaptan in children and 
adolescent subjects hospitalized with euvolemic or 
hypervolemic hyponatremia.
Pediatric and adolescent subjects who are diagnosed with 
euvolemic or hypervolemic hyponatremia (serum sodium 
< 130 mEq/L [mmol/L]) that persists despite initial standard 
background therapy (eg, including fluid restriction) are eligible 
to be screened for participation in this trial.  Subjects who 
demonstrate prior resistance to vasopressin antagonist therapy 
will be excluded.  All potential subjects must be deemed by the 
investigator as likely to benefit from a therapy that raises serum 
sodium levels.
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 this protocol, persistent hyponatremia will be 
defined as serum sodium assessments < 130 mEq/L (mmol/L)


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documented as present for at least 48 hours.  Specifically, 
subjects must have at least 2 documented serum sodium 
assessments < 130 mEq/L (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 mEq/L (mmol/L), 
which will serve as the baseline value for final trial 
qualification and clinical management strategy, is to be 
obtained within 2-4 hours prior to the first dose of tolvaptan.  
Additional qualification assessments will be performed as per 
etiology of hyponatremia.  The first dose of tolvaptan will be 
administered upon successful completion of all screening 
procedures.
Subjects will be required to be in a hospital setting during 
initiation and titration of tolvaptan.
Overall, in this trial, subjects will undergo treatment (2 to 
5 days of tolvaptan among 2 treatment phases) and a post-last 
dose follow-up phase of 14 days.
Treatment Phase A
After screening, all subjects will initially receive tolvaptan once 
daily for 2 days.  If the desired serum sodium level target 
improvement is not reached after Day 2 of tolvaptan 
administration (post 2 doses), a third day (Day 2a) of treatment 
is required.  At the end of Day 2 (or 2a), subjects will be 
assessed for a serum sodium level change of ≥ 4 mEq/L 
(mmol/L).  At that time, subjects who are responders will enter 
Treatment Phase B, and be randomized to either the Early 
Withdrawal group or Late Withdrawal group.  Responders are 
defined as those subjects who achieve an increase in serum 
sodium concentrations of ≥ 4 mEq/L (mmol/L); nonresponders 
are defined as subjects who do not achieve an increase in serum 
sodium concentration of ≥ 4 mEq/L (mmol/L). 
Treatment Phase B  
Responders
Responders from Treatment Phase A will be randomized to 
either the:

Late Withdrawal group - subjects continue tolvaptan 
treatment on Days 3 and 4

Early Withdrawal group - subjects do not receive additional 
tolvaptan treatment on Days 3 and 4.
Randomization will include stratification by age 
 
 
, serum sodium response 
 


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, and underlying etiology of 
hyponatremia.  
Subjects who are randomized to the Early Withdrawal group 
will initially be observed to determine whether additional 
intervention is required to maintain appropriate serum sodium 
levels.  Those subjects whose serum sodium level declines by 
4 mEq/L (mmol/L), or whose overall clinical condition 
requires further treatment to increase serum sodium level, will 
be treated per the investigator’s preferred standard of care.  Any 
intervention intended to raise serum sodium level during the 
first 48 hours of the Early Withdrawal phase (including fluid 
restriction) will be defined as rescue therapy. Subjects who 
receive rescue therapy will be considered to have reached their 
clinical endpoint, and their data will be censored from that time 
forward.
Nonresponders
If the subject remains a nonresponder at the end of Day 2a, the 
investigator decides to either (a) continue tolvaptan for 2 
additional days, or (b) discontinue tolvaptan and treat the 
subject per the investigator’s preferred standard of care during 
Days 3 and 4.  Subjects will continue to follow scheduled 
assessments regardless of treatment.
All Subjects
All subjects will have serum sodium levels measured at 8, 12, 
and 24 hours post-first dose and thereafter every 12 (± 4) hours 
through completion of Treatment Phase B.  In addition to serum 
sodium samples obtained for treatment qualification and 
efficacy endpoints, supplemental samples for the purposes of 
safety assessment will be obtained on Day 1 at 4 to 6 (-1 to 
+ 0.25) hours postdose and at 18 (± 1) hours postdose.  This 
sodium safety assessment will be repeated at 6 (-1 to + 0.25)
and 18 (± 1) hours postdose each day for the remainder of 
titration.  
Follow-up Phase C  
All subjects will have an additional serum sodium assessment at 
72 (4) hours post-last dose and 7 (+ 1) days post-last dose.  A 
final safety follow-up telephone contact/visit will be performed 
14 (+ 2) days post-last dose.
Pharmacokinetic Sampling
Blood samples for PK analysis will be obtained at 2 and 8 hours 
post-first dose, and at trough (24 [4] hours post-previous 


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dose)  on Days 1, 2, 3, and 4 for all subjects dosed with 
tolvaptan on Days 1, 2, 3, and 4, respectively, regardless of 
responder status.  Pharmacokinetic profiles will be evaluated on 
an ongoing basis to determine variability among subjects.  
Based on the findings, PK sampling will continue for as long as 
necessary to establish suitable estimates of clearance with a 
90% confidence interval (CI), similar to that observed in adult 
subject populations.  Once these estimates are achieved, 
sampling will be discontinued in subsequent subjects in order to 
minimize blood draws in this pediatric population.
Subject Population:
This trial will enroll approximately 100 male and female 
subjects to get approximately 70 randomized subjects aged 
4 weeks (or 44 weeks adjusted gestational age) to 
< 18 years who have been diagnosed with euvolemic or 
hypervolemic hyponatremia (< 130 mEq/L [mmol/L]) that 
persists despite initial standard background therapy (including 
fluid restriction and excluding a vasopressin antagonist).  Age 
groups will be enrolled such that at least 50% of these subjects 
will be < 10 years old and at least 25% of subjects < 6 years 
old.  
Subjects with acute hyponatremia or hyponatremia expected to 
resolve spontaneously will be excluded from the trial.  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 
excluded from the trial if this is not possible.
The protocol entry criteria 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 
syndrome of inappropriate secretion of antidiuretic 
hormone/other, 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.
Inclusion/Exclusion 
Criteria:
Key inclusion criteria:

Male and female subjects 4 weeks (or 44 weeks 
adjusted gestational age) to < 18 years old

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 


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investigator as likely to benefit from a therapy that raises 
serum sodium levels

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 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 final trial qualification and 
clinical management strategy, is to be obtained within
2-4 hours prior to the first dose of tolvaptan
Key exclusion criteria:

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, then volume status should be specifically 
clinically assessed to rule out volume depletion

Has serum sodium level < 120 mEq/L (mmol/L), with or 
without associated neurologic impairment (ie, symptoms 
such as apathy, confusion, or seizures)

Current use or expected use during the trial of potent 
cytochrome P450 (CYP) 3A4 inhibitors in subjects < 12 kg 
or moderate CYP3A4 inhibitors in subjects < 6 kg

Has estimated glomerular filtration rate 
(eGFR) < 30 mL/min/1.73 m2

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

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

Has uncontrolled diabetes mellitus defined as fasting 


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glucose > 300 mg/dL (16.7 mEq/L [mmol/L])

Has screening liver function values > 3 the upper limit of 
normal (ULN)

Subjects who have cirrhosis and meet any of the following 
conditions:  a major gastrointestinal (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
Trial Sites:
The trial will be conducted at approximately 60 centers 
globally.
Investigational 
Medicinal Product, 
Dose, Formulation, 
Mode of 
Administration:
Tolvaptan will be supplied as 3.75-, 7.5-, 15-, and 30-mg 
spray-dried tablets and, where approved, as a 1 mg/mL 
(0.1% w/v) suspension.  
Tolvaptan tablets 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 of tolvaptan will be 
given with 60 mL of water.  The treatment duration will be up 
to 5 days.  
Tolvaptan suspension will be administered once daily, orally 
using the provided, appropriately-sized syringe (3 mL or 
10 mL) to measure the volume.  The lowest volume that can be 
administered is 0.3 mL (0.3 mg).
Any initiation or titration of tolvaptan must occur in a hospital 
setting.
The investigator has the option of performing a swallow test 
and providing coaching on swallowing techniques using 
placebo tablets if it is unknown if the subject is able to swallow 
tablets.  Placebo tablets will be provided for use in performing 
this test at screening.
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 and at > 20 hours following each additional dose; a 
change in serum sodium 4 mEq/L (mmol/L) from baseline 
should warrant up-titration, which is limited to no more than 
twice the previous dose.

Subjects ≥ 4 weeks (or ≥ 44 weeks adjusted gestational age) 


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to < 2 years of age and weighing ≥ 3 kg to < 6 kg will 
receive 0.1 mg/kg of the suspension on Day 1 with possible 
up-titration to 0.2 mg/kg and 0.4 mg/kg doses.

Subjects ≥ 4 weeks (or ≥ 44 weeks adjusted gestational age) 
to < 2 years of age and  weighing ≥ 6 kg to < 12 kg will 
receive 0.1 mg/kg of the suspension on Day 1 with possible 
up-titration to 0.2 mg/kg and 0.4 mg/kg doses. 

Subjects 2 to ≤ 6 years of age, weighing ≤ 30 kg will 
receive a 0.15 mg/kg dose of the suspension on Day 1 with 
possible up-titration to 0.3 mg/kg and 0.6 mg/kg doses.

Subjects > 6 years of age, weighing ≤ 30 kg and who cannot 
safely swallow a tablet, will receive a 0.15 mg/kg dose of 
the suspension on Day 1 with possible up-titration to 
0.3 mg/kg and 0.6 mg/kg doses.

Subjects > 6 years of age and weighing 20 to 50 kg, 
inclusive, will receive a 7.5 mg tablet on Day 1 with 
possible up-titration to 15-mg and 30-mg doses.

Subjects > 6 years of age and weighing > 50 kg, will
receive a 15 mg tablet on Day 1 with possible up-titration to 
30-mg and 60-mg doses.
The subjects will continue dosing according to a titration 
scheme targeting a final serum sodium concentration between 
135 and 140 mEq/L (mmol/L).  Titration will ideally achieve a 
change in serum sodium concentration of at least 4 to 8 mEq/L 
(mmol/L)/24 hours but not exceeding 


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Trial Assessments:
Efficacy:

Serum sodium concentrations
Pharmacokinetic/pharmacodynamic:

Blood sampling for tolvaptan and metabolite plasma 
concentrations

Fluid intake

Urine output 

Urine chemistry
Safety:

Adverse event (AE) reporting

Vital signs

Clinical laboratory tests (hematology, coagulation, 
chemistry, urinalysis)

Physical examinations, including body weight and
neurological examinations
Criteria for 
Evaluation:
Primary Efficacy Endpoint

For subjects with serum sodium level increases of 
4 mEq/L (mmol/L) (ie, responders), change in serum 
sodium concentration from Day 2 (or 2a) at the end of 
Treatment Phase A to the end of Treatment Phase B for 
Early compared to Late Withdrawal groups.
Key Secondary Efficacy Endpoint

For all subjects, the key secondary endpoint is the 
change in serum sodium concentration at the end of 
Day 2 (or 2a) in Treatment Phase A from baseline.  
Other Secondary Endpoints
Safety:

Percentage of subjects with overly rapid increase in 
serum sodium level 
 

Change in serum sodium level from 24 hours post-last 
dose to 7 days post-last dose

Percentage of subjects requiring rescue therapy (other 
than fluid restriction) during Treatment Phase A and 
Treatment Phase B 

Percentage of subjects requiring fluid restriction during 
Treatment Phase A and Treatment Phase B 

Vital signs, blood pressure, clinical laboratory tests, 


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body weight, and neurological examinations
Pharmacokinetic:

On Day 1 in Treatment Phase A, tolvaptan maximum 
(peak) plasma concentration (Cmax), time to maximum 
(peak) plasma concentration (tmax), and area under the 
concentration-time curve from time zero to 24 hours 
(AUC0-24h)
Pharmacodynamic:

Fluid intake, urine output, and fluid balance 
(intake minus output) every 6 hours on Days 1 and 2 in 
Treatment Phase A
Exploratory Endpoints

Efficacy will be assessed in nonresponders continuing 
on tolvaptan therapy by change from baseline in serum 
sodium concentration at the end of Treatment Phase B
compared to the end of Treatment Phase A. 

In all subjects, 24-hour excretion of sodium, creatinine, 
and osmolality on Days 1 and 2

24-hour sodium clearance on Day 1

Quality of life (QoL) assessments
Statistical Methods:
The primary analysis will use a mixed-model repeated 
measures analysis based on the observed cases dataset.  The key 
secondary analysis will be analyzed using a paired Student’s 
t-test.  Other secondary analyses will use a paired Student’s 
t-test, descriptive statistics, and/or 2-sided 95% CIs.
Trial Duration:
Overall trial duration of enrollment is expected to be
approximately 3 years with an enrollment rate of approximately
33 subjects per year.  Nominal trial duration for each subject is 
up to 21 days.  Treatment duration is up to 5 days with ongoing 
monitoring of serum sodium levels.  A serum sodium 
assessment and AE follow-up visit will be performed 7 (+ 1) 
days post-last dose. A final safety follow-up telephone contact 
or visit will be performed 14 (+ 2) days post-last dose.


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Table of Contents 
Otsuka Pharmaceutical Development & Commercialization, Inc............1
Protocol Synopsis...........................................................................................2
Table of Contents...........................................................................................2
List of In-text Tables .....................................................................................2
List of In-text Figures....................................................................................2
List of Appendices..........................................................................................2
List of Abbreviations and Definitions of Terms .........................................2
1
Introduction ..........................................................................................2
1.1
Nonclinical Data..................................................................................................2
1.1.1
Juvenile Animal Toxicity Data.........................................................................2
1.2
Clinical Data........................................................................................................2
1.2.1
Pharmacokinetics..............................................................................................2
1.2.2
Pharmacodynamics...........................................................................................2
1.2.3
Clinical Efficacy...............................................................................................2
1.3
Known and Potential Risks and Benefits ............................................................2
2
Trial Rationale and Objectives............................................................2
2.1
Trial Rationale.....................................................................................................2
2.1.1
Dosing Rationale ..............................................................................................2
2.2
Trial Objectives...................................................................................................2
2.2.1
Primary Objective.............................................................................................2
2.2.2
Secondary Objectives .......................................................................................2
3
Trial Design...........................................................................................2
3.1
Type/Design of Trial ...........................................................................................2
3.1.1
Trial Phases.......................................................................................................2
3.2
Trial Treatments ..................................................................................................2
3.2.1
Tablet Formulation ...........................................................................................2
3.2.2
Suspension Formulation ...................................................................................2
3.2.3
Dosing Guidelines ............................................................................................2
3.2.4
Titration Guidelines and Rescue Therapy ........................................................2
3.3
Trial Population...................................................................................................2


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3.3.1
Subject Eligibility by Hyponatremia Etiology .................................................2
3.4
Eligibility Criteria................................................................................................2
3.4.1
Informed Consent/Assent .................................................................................2
3.4.2
Inclusion Criteria ..............................................................................................2
3.4.3
Exclusion Criteria.............................................................................................2
3.5
Outcome Variables..............................................................................................2
3.5.1
Primary Efficacy Outcome Variable ................................................................2
3.5.2
Key Secondary Efficacy Outcome Variable.....................................................2
3.5.3
Other Secondary Outcome Variables ...............................................................2
3.5.4
Exploratory Variables.......................................................................................2
3.6
Measures to Minimize/Avoid Bias......................................................................2
3.7
Trial Procedures ..................................................................................................2
3.7.1
Schedule of Assessments..................................................................................2
3.7.2
Efficacy Assessments .......................................................................................2
3.7.3
Pharmacokinetic/Pharmacodynamic Assessments ...........................................2
3.7.4
Safety Assessments...........................................................................................2
3.7.5
End of Trial.......................................................................................................2
3.7.6
Independent Data Monitoring Committee........................................................2
3.8
Stopping Rules, Withdrawal Criteria and Procedures.........................................2
3.8.1
Entire Trial or Treatment Arm(s) .....................................................................2
3.8.2
Individual Site...................................................................................................2
3.8.3
Individual Subject Discontinuation ..................................................................2
3.9
Screen Failures ....................................................................................................2
3.10
Definition of Completed Subjects.......................................................................2
3.11
Definition of Lost to Follow-up ..........................................................................2
3.12
Subject Compliance.............................................................................................2
3.13
Protocol Deviations.............................................................................................2
4
Restrictions............................................................................................2
4.1
Prohibited Medications........................................................................................2
4.2
Other Restrictions................................................................................................2
5
Reporting of Adverse Events...............................................................2
5.1
Definitions...........................................................................................................2


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5.2
Eliciting and Reporting Adverse Events .............................................................2
5.3
Immediately Reportable Events ..........................................................................2
5.3.1
Hyponatremia-related Adverse Events.............................................................2
5.4
Potential Drug-induced Liver Injury...................................................................2
5.4.1
Liver Transaminase Elevations.........................................................................2
5.5
Pregnancy............................................................................................................2
5.6
Procedure for Breaking the Blind........................................................................2
5.7
Follow-up of Adverse Events..............................................................................2
5.7.1
Follow-up of Nonserious Adverse Events........................................................2
5.7.2
Follow-up of Serious Adverse Events ..............................................................2
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring After 
Last Scheduled Contact ....................................................................................2
6
Pharmacokinetic/Pharmacodynamic Analyses .................................2
6.1
Pharmacokinetic Analysis...................................................................................2
6.2
Pharmacodynamic Analysis ................................................................................2
7
Statistical Analysis................................................................................2
7.1
Sample Size.........................................................................................................2
7.1.1
Sample Size for Efficacy ..................................................................................2
7.1.2
Sample Size for Pharmacokinetic Parameters..................................................2
7.2
Datasets for Analysis...........................................................................................2
7.3
Handling of Missing Data ...................................................................................2
7.4
Primary and Secondary Outcome Analysis.........................................................2
7.4.1
Primary Outcome Analysis...............................................................................2
7.4.2
Secondary Outcome Analyses ..........................................................................2
7.4.3
Exploratory Outcome Analyses........................................................................2
7.4.4
Interim Analysis................................................................................................2
7.5
Analysis of Demographic and Baseline Characteristics......................................2
7.6
Safety Analysis....................................................................................................2
7.6.1
Adverse Events .................................................................................................2
7.6.2
Clinical Laboratory Assessment Data ..............................................................2
7.6.3
Physical Examination and Vital Signs Data .....................................................2
8
Management of Investigational Medicinal Product..........................2


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8.1
Packaging and Labeling ......................................................................................2
8.2
Storage.................................................................................................................2
8.3
Accountability .....................................................................................................2
8.4
Returns and Destruction......................................................................................2
8.5
Reporting of Product Quality Complaints...........................................................2
8.5.1
Eliciting and Reporting Product Quality Complaints.......................................2
8.5.2
Information Required for Reporting Purposes .................................................2
8.5.3
Return Process ..................................................................................................2
8.5.4
Assessment/Evaluation.....................................................................................2
9
Records Management...........................................................................2
9.1
Source Documents...............................................................................................2
9.2
Data Collection....................................................................................................2
9.3
File Management at the Trial Site.......................................................................2
9.4
Records Retention at the Trial Site......................................................................2
10
Quality Control and Quality Assurance.............................................2
10.1
Monitoring...........................................................................................................2
10.2
Auditing...............................................................................................................2
11
Ethics and Responsibility.....................................................................2
12
Confidentiality ......................................................................................2
13
Amendment Policy................................................................................2
14
Publication Authorship Requirements...............................................2
15
References..............................................................................................2


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List of In-text Tables
Table 2.1.1-1
Starting Tolvaptan Tablet Doses as mg/kg of Body Weight ...........2
Table 3.2.3-1
Starting Tolvaptan Doses With or Without Potent or 
Moderate CYP3A Inhibitors............................................................2
Table 3.3.1.2-1
Screening Algorithms by Hyponatremia Etiology...........................2
Table 3.4.2-1
Inclusion Criteria .............................................................................2
Table 3.4.3-1
Exclusion Criteria ............................................................................2
Table 3.7-1
Schedule of Assessments.................................................................2
Table 3.7.2.1-1
Serum Sodium Assessments ............................................................2
Table 3.7.4.2.3-1
Clinical Laboratory Tests to be Performed Locally.........................2
Table 4.1-1
List of Cytochrome P450 3A4 Inhibitors (Partial List) ...................2
Table 7.4.4-1
Sample Size Re-estimation ..............................................................2


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List of In-text Figures
Figure 1.2.3-1
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) ............................................................................2
Figure 1.2.3-2
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).....................2
Figure 3.1-1
Trial Design Schematic....................................................................2
Figure 3.2.4-1
Titration and Rescue Therapy Scheme ............................................2


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List of Appendices
Appendix 1
Names of Sponsor Personnel ...........................................................2
Appendix 2
Institutions Concerned With the Trial..............................................2
Appendix 3
Handling and Shipment of Bioanalytical Samples ..........................2
Appendix 4
Tanner Staging.................................................................................2
Appendix 5
Protocol Amendments......................................................................2


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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
AKI
Acute kidney injury
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC
Area under the concentration-time curve
AUC0-24h
Area under the concentration-time curve from time zero to 24 hours
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
BUN
Blood urea nitrogen
BW
Body weight
CHF
Congestive heart failure
CI
Confidence interval
CL/F
Apparent clearance of drug from plasma after extravascular 
administration
Cmax
Maximum (peak) plasma concentration
CV
Coefficient of variation
CYP
Cytochrome P450
DDAVP
1-deamino-8-D-arginine vasopressin
DILI
Drug-induced liver injury
ECG
Electrocardiogram
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
FENa
Fractional excretion of sodium
FE urea
Fractional excretion of urea
GCP
Good Clinical Practice
GI
Gastrointestinal
HF
Heart failure
HFI
Hereditary fructose intolerance
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICU
Intensive care unit
IDMC
Independent data monitoring committee
IEC
Independent ethics committee


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IMP
Investigational medicinal product
IND
Investigational new drug
INR
International normalized ratio
IRB
Institutional review board
IRE
Immediately reportable event
ITT
Intent-to-treat
IV
Intravenous
IWRS
Interactive web response system
Ki
Inhibition constant
LOCF
Last observation carried forward
LS
Least squares
MHRA
Medicines and Healthcare Products Regulatory
MMRM
Mixed-model repeated measures
OAPI-EQC
Otsuka America Pharmaceutical, Inc.-Ethics, Quality and
Compliance
OC
Observed cases
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc.
PD
Pharmacodynamic(s)
PDCO
Paediatric Committee
PI
Principal investigator
PK
Pharmacokinetic(s)
PO
By mouth
PQC
Product quality complaint
PREA
Pediatric Research Equity Act
QoL
Quality of life
RBC
Red blood cell
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
SAP
Statistical analysis plan
SD
Standard deviation
SIADH
Syndrome of inappropriate secretion of antidiuretic hormone
STAT
Immediate
t1/2,z
Terminal-phase elimination half-life
TEAE
Treatment-emergent adverse event
tmax
Time to maximum (peak) plasma concentration
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBC
White blood cell
WOCBP
Women of childbearing 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 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.2,3
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.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 neurological 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, gender, 
baseline neurological 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 due to their relatively immature renal function, increased insensible water 
loss, and their 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 either euvolemic 
or hypervolemic hyponatremia are CHF, 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) has required pediatric 
trials be conducted for tolvaptan for the indication of hyponatremia.  This trial will assess 
the short-term safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of 
tolvaptan in children and adolescent subjects with euvolemic or hypervolemic 
hyponatremia.
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 


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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/h 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.13,14
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 
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 QTc interval when compared to the control group.  In an action potential 


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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 
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 


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nonclinical studies conducted with tolvaptan can be found in the current version of the 
Investigator’s Brochure (IB).14
1.1.1
Juvenile Animal 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.14
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 1000 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 
observed adverse effect level in both males and females was judged to be 
30 mg/kg/day.14
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 


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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 HF 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 and multinationally; 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.  As of 31 Mar 2015, the tolvaptan clinical development 
program consists of 105 trials; 97 trials had been completed worldwide, 4 trials were 
terminated because of slow enrollment, and 8 trials were ongoing.  More information is 
available in the IB.14
1.2.1
Pharmacokinetics
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 (t1/2,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 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.14
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 


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dose and apparent clearance of drug from plasma after extravascular administration 
(CL/F) values are unchanged for single doses of 30 to 480 mg.14
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%).
In healthy subjects, tolvaptan pharmacokinetics following a 15 mg dose as a 1 mg/mL 
suspension shows a more rapid absorption (the median tmax is shorter, 1.00 versus 
2.00 hours respectively), when compared to a 15 mg tablet.  The geometric mean ratio 
(90% CI), for suspension over the tablet, for Cmax is 1.614 (1.484 to 1.754) but AUC is 
unchanged.14
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%.14
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 


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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 were observed.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.14
1.2.2
Pharmacodynamics
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 serum osmolality, and 
increased plasma AVP concentrations and renin activity, but no dose-related increases 
were observed for any other parameter.
When compared to a 15-mg spray-dried tablet, the pharmacodynamic profiles of urine 
excretion rate, cumulative urine volume, free water clearance, urine osmolality, and 
serum sodium were not different for 15-mg of the suspension.14
Details of the currently available PK/PD data for the compound are available in the IB.14


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1.2.3
Clinical Efficacy
Thirteen trials involving either exclusive evaluation of adult 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 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 greater 
decreases in body weight compared to placebo.  Additionally, subjects with liver disease 
responded to higher doses of tolvaptan with reductions in body weight.14
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.  Subjects 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 1.2.3-1), but recovered upon resumption of tolvaptan 
therapy (Figure 1.2.3-2).


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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
Figure 1.2.3-1
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)
7DFU = 7-day follow-up.


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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 1.2.3-2
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)
Details of the currently available efficacy data for tolvaptan are available in the IB.14
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.  The extent of 
exposure to oral tolvaptan by dose in the pooled database (N = 7373) comprises
3115 subjects in trials for heart failure (HF), 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. As of 31 Mar 2014, additionally, 
14 healthy adult subjects were also exposed to the tolvaptan suspension formulation.14
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.


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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 TEAE 
(> 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 the spray-dried tablet and suspension formulation 
of tolvaptan during clinical trials.14
There is the potential for osmotic diarrhea due to the sorbitol content in the suspension.  
D-Sorbitol is a hexahydric sugar alcohol that naturally occurs in fruits and animal tissue.  
The daily per capita consumption of sorbitol as a food ingredient is approximately 
200 mg.  The compound is about 35-60% as sweet as sugar, and has been the impetus as 
a substitute for sugar to reduce caloric intake and prophylactic measures against the
formation of dental caries. Absorption of sorbitol by humans is limited by its rate of
diffusion from the GI tract and by laxation that may occur after ingestion of high doses.  
Typically, 25-50 g in adults may cause osmotic diarrhea.  The corresponding dose in 
children is thought to be 10 g and higher, but is dependent on body weight and types of 
foods ingested. Similar findings are also observed with other sugar alcohols, eg, 
xylitol.16
Following a single 15 mg tolvaptan dose of the suspension, containing 8 g of sorbitol, in 
healthy adults, no diarrhea was reported.14
Therefore, in this trial, suspension dosing is limited to subjects who weigh ≤ 30 kg; the 
maximum dose of sorbitol is expected to be approximately 9.6 grams in a 0.6 mg/kg dose 
for a subject who weighs 30 kg. Subjects will be started on the lowest dose for their 
weight and titrated to higher doses as appropriate for their clinical condition.  Subjects 
will be in a hospital setting during titration and will be closely monitored for rate of 
sodium correction and signs of dehydration including diarrhea.
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 


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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.
Retrospective evaluation of data from the hyponatremia and HF 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 subjects
treated with tolvaptan are at a potential increased risk for liver injury.  Further details 
regarding this issue can be found in the IB.14
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 HF, 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 HF 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 HF 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.14  To date, no clinical trials in 
children have been completed with tolvaptan.


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2
Trial Rationale and Objectives
2.1
Trial Rationale
The purpose of this trial is to establish the effects of tolvaptan on serum sodium 
concentration as well as the safety of use of tolvaptan in children and adolescents with 
euvolemic or hypervolemic hyponatremia secondary to 
 
.  In addition, blood samples will be taken to 
determine tolvaptan PK specific to a pediatric population, as the absorption, distribution, 
metabolism, and elimination of drugs in children and adolescents can vary from that of 
adults.  These differences can be due to differences in physiology based on maturity 
status (eg, GI transit times are faster, the ratio of total body water to body fat is shifting, 
and the expression of drug metabolizing enzymes change) or based on underlying disease 
state.17  Hyponatremia alone does not appear to affect tolvaptan PK; however, tolvaptan 
exposure is 2-fold greater in adult subjects with CHF compared to healthy adult subjects 
and clearance appears to decrease about 50% in subjects with moderate to severe hepatic 
failure (Child-Pugh score > 6).  As the primary pharmacodynamic effect of tolvaptan is to 
produce an increase in urine output (aquaresis), urine output and fluid intake will be 
determined as PD endpoints.14
The proposed population size of 100 subjects is expected to yield 70 subjects who 
respond to tolvaptan (henceforth termed “responders”), which has adequate power 
(> 90%) to test for statistical significance in the primary endpoint.  Enrollment is 
expected to take approximately 3 years using approximately 60 sites globally.  Additional 
blood sampling will be included across populations to provide PK information.
Even with a limited size, recruitment for such a trial is expected to be challenging due to 
the low frequency of AVP-mediated hyponatremia in children.  Therefore, the trial will 
be organized at major pediatric referral centers to access the largest patient population.
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.18


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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.19  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.
2.1.1
Dosing Rationale
Enrolled subjects will be dosed based on formulation type, age, weight, and the use of 
CYP3A4 inhibitors.
In the pivotal hyponatremia trials14,20,21 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 use of tolvaptan tablets in this 
trial were selected to produce mg/kg doses of tolvaptan within the range observed for the 
adult trials.  Table 2.1.1-1 outlines the mg/kg dose ranges for tolvaptan tablet doses and 
body weights of 10, 20, 50, 70 (standard adult man), and 100 kg.
Table 2.1.1-1
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.
Tolvaptan is metabolized by the CYP3A isozyme.  At birth, the amount of CYP3A per 
gram of liver is less than in an adult, but adult levels of CYP3A are reached by 2 years of 
age.  A physiologically-based pharmacokinetic model of adult tolvaptan concentrations 
was modified to estimate tolvaptan concentrations in subjects from ≥ 4 weeks 
(or ≥44 weeks of adjusted gestational age) to < 2 years of age and in subjects 2 to 
< 4 years of age.22  It was estimated that doses of 0.1 mg/kg and 0.15 mg/kg, 
respectively, of the suspension would produce peak tolvaptan concentrations similar to 
those produced by a 15 mg tablet in an adult subject.  However, overall exposure for the 
suspension as determined by AUC would be 33% and 13% lower, respectively, for 
subjects < 2 years of age and subjects 2 to < 4 years of age when compared to a 15 mg 
tablet in an adult.  It is expected that a 0.15 mg/kg starting dose of tolvaptan suspension 
would also be suitable for children > 4 years of age, as CYP3A expression would be the 
same as for children ≥ 2 to 4 years of age.  Suspension will only be administered to 


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children who weigh 30 kg or less to limit the amount of sorbitol administered; a 30 kg 
child titrated to a 0.6 mg/kg dose of tolvaptan suspension would receive 18 mL of 
tolvaptan suspension, containing approximately 9.6 g of sorbitol.
Tolvaptan is a sensitive CYP3A4 substrate; plasma concentrations increased 
approximately 4-fold when tolvaptan was administered with the potent CYP3A4 inhibitor 
ketoconazole.14,23  Where appropriate dose reductions are possible, tolvaptan doses may 
be coadministered with potent or moderate CYP3A4 inhibitors. Table 3.2.3-1 outlines 
starting dose adjustments when tolvaptan is administered concurrently with potent or 
moderate CYP3A inhibitors.
2.2
Trial Objectives
2.2.1
Primary Objective
The primary objective is to demonstrate that tolvaptan effectively and safely increases 
and maintains serum sodium concentrations in children and adolescent subjects with 
euvolemic or hypervolemic hyponatremia.
2.2.2
Secondary Objectives
The key secondary objective is to assess the PK of tolvaptan and the effect on fluid 
balance in children and adolescent subjects with euvolemic or hypervolemic 
hyponatremia.
3
Trial Design
3.1
Type/Design of Trial
This is an open-label, multicenter, multiple-dose, randomized withdrawal, parallel-group 
trial of tolvaptan in children and adolescents hospitalized with chronic euvolemic or 
hypervolemic hyponatremia (serum sodium < 130 mEq/L [mmol/L]) persisting despite 
initial standard therapy.  A schematic of the trial design is provided in Figure 3.1-1.


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Serum Sodium
< 4 mEq/L = 
Nonresponder
Serum Sodium
≥4 mEq/L = 
Responder
PI = Principal investigator.
Figure 3.1-1
Trial Design Schematic


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3.1.1
Trial Phases
Screening should be performed on Days −2 to −1 to confirm eligibility, followed by the 
3 trial phases described in Section 3.7.1.
3.1.1.1
Treatment Phase A 
All subjects will initially receive tolvaptan once daily on Days 1 and 2.  If a subject’s 
serum sodium level has not increased by at least 4 mEq/L (mmol/L) by Day 2, an 
additional day of treatment is required and is referred to as Day 2a. If subjects do not 
achieve an increase in serum sodium concentration of 4 mEq/L (mmol/L) on Day 2a, 
they will be defined as nonresponders.  If subjects achieve an increase in serum sodium 
concentration of 4 mEq/L (mmol/L) on Day 2 (or 2a) they will be defined as 
responders.
3.1.1.2
Treatment Phase B
On Day 3 responders will be randomized (Section 3.1.1.2.1) to either the Early 
Withdrawal group or the Late Withdrawal group.  Nonresponders will not be randomized.
For nonresponders from Treatment Phase A, the investigator will determine if the subject 
is to either: 

Continue treatment with study drug or 

Prescribe treatment per local standard of care for Days 3 and 4.
3.1.1.2.1
Randomization
Responders will be randomized to either: 

Late Withdrawal group - subjects continue tolvaptan treatment on Days 3 and 4

Early Withdrawal group - subjects do not receive additional tolvaptan treatment 
on Days 3 and 4.
Randomization will be stratified by age 
 
, serum 
sodium response 
, and underlying hyponatremia etiology
. 
Subjects randomized to the Early Withdrawal group will be observed to determine 
whether additional intervention is required to maintain appropriate serum sodium levels.  
Subjects whose serum sodium declines by 4 mEq/L (mmol/L) or whose overall clinical 
condition requires further treatment to raise serum sodium levels should be treated per 
local standard of care.  Any intervention intended to raise serum sodium concentration 
during the first 48 hours of the Early Withdrawal phase (including fluid restriction) will 
be defined as rescue therapy.  Subjects receiving rescue therapy will be considered to 


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have reached their clinical endpoint, and their data will be censored from that time 
forward.
3.1.1.3
Follow-up Phase C
All subjects will have an additional serum sodium measurement at 72 (4) hours 
post-last dose and 7 (+ 1) days post-last dose.  A final safety follow-up telephone 
contact/visit will be performed 14 (+ 2) days post-last dose.
3.2
Trial Treatments
3.2.1
Tablet Formulation
Tolvaptan tablets will be administered orally once daily, preferably in the morning hours, 
with a dose proportional amount of water, as follows:

Doses of 15 mg tolvaptan will be given with 240 mL of water.

Doses of 7.5 mg tolvaptan will be given with 120 mL of water.

Doses of 3.75 mg of tolvaptan will be given with 60 mL of water.
The treatment duration will be up to 5 days.  Any initiation or titration of tolvaptan must 
occur in a hospital setting.
The maximum starting doses, by weight, age, and CYP3A inhibitor, for subjects are 
shown in Table 3.2.3-1 and are within the range previously used in trials involving adult 
hyponatremic subjects.
The investigator has the option of performing a swallow test and providing coaching on 
swallowing techniques using placebo tablets if it is unknown if the subject is able to 
swallow tablets.  Placebo tablets will be provided for use in performing this test during
screening.
3.2.2
Suspension Formulation
Tolvaptan suspension, 1 mg/mL (0.1% w/v), will be administered orally once daily, 
preferably in the morning hours.  The treatment duration will be up to 5 days.  Any 
initiation or titration of tolvaptan must occur in a hospital setting.
The maximum starting doses for subjects, by weight, age, and CYP3A inhibitor are 
shown in Table 3.2.3-1.
3.2.3
Dosing Guidelines
Subjects will be administered tolvaptan on a formulation, age- and weight-based scale.  


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Table 3.2.3-1 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.  As the smallest volume of suspension that can be 
administered is 0.3 mL (0.3 mg), subjects weighing < 3 kg, < 6 kg and taking a moderate 
or a potent CYP3A4 inhibitor, or weighing < 12 kg and taking a potent CYP3A4 
inhibitor may not be enrolled.  Suspension should be administered with the syringes 
provided.
Table 3.2.3-1
Starting Tolvaptan Doses With or Without Potent or Moderate 
CYP3A Inhibitors
Age/Weight
Can subject 
swallow a 
tablet?
Starting Dose:  No
CYP Inhibitor
Starting Dose:  
Moderate CYP 
Inhibitor
Starting Dose:  
Potent CYP 
Inhibitor
≥4 wk (or ≥44 wk 
adjusted gestational 
age) to < 2 y AND 
≥3 kg to < 6 kgc
N/A
0.1 mg/kg 
suspensiona,b
Not eligible for 
treatment
Not eligible for 
treatment
≥4 wk (or ≥44 wk 
adjusted gestational 
age) to < 2 y AND 
≥6 to < 12 kgc
N/A
0.1 mg/kg 
suspensiona,b
0.05 mg/kg 
suspension
Not eligible for 
treatment
≥2 y  to ≤6 y AND 
≤30 kgc
N/A
0.15 mg/kg 
suspension
0.08 mg/kg 
suspension
0.04 mg/kg 
suspension
> 6 y AND ≤30 kg
No
0.15 mg/kg 
suspension
0.08 mg/kg 
suspension
0.04 mg/kg 
suspension
> 6 y AND 20 to 
50 kg
Yes
7.5 mg tablet
3.75 mg tablet
1.90 mL suspension
> 6 y AND > 50 kg
Yes
15 mg tablet
7.5 mg tablet
3.75 mg tablet
a The smallest volume of suspension that may be administered is 0.3 mL (0.3 mg), therefore dose 
reductions cannot be accommodated for children < 6 kg taking moderate inhibitors and for children < 12 kg 
taking potent inhibitors.
b Tolvaptan suspension is provided in a concentration of 1 mg/mL.
c Suspension required (pediatric subjects ≤ 6 years of age and ≤ 30 kg body weight).
Titration of tolvaptan doses can occur once daily 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 24 (± 4) hours of the previous dose.  Up-titration is limited 
to no more than twice the previous dose.

Subjects ≥ 4 weeks (or ≥ 44 weeks adjusted gestational age) to < 2 years of 
age and weighing ≥ 3 kg to < 6 kg will receive 0.1 mg/kg of the suspension on 
Day 1 with possible up-titration to 0.2 mg/kg and 0.4 mg/kg doses.

Subjects ≥ 4 weeks (or ≥ 44 weeks adjusted gestational age) to < 2 years of 
age and weighing ≥ 6 kg to < 12 kg will receive 0.1 mg/kg of the suspension 
on Day 1 with possible up-titration to 0.2 mg/kg and 0.4 mg/kg doses. 


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
Subjects 2 to ≤ 6 years of age, weighing ≤ 30 kg will receive a 0.15 mg/kg 
dose of the suspension on Day 1 with possible up-titration to 0.3 mg/kg and 
0.6 mg/kg doses.

Subjects > 6 years of age, weighing ≤ 30 kg and who cannot safely swallow a 
tablet, will receive a 0.15 mg/kg dose of the suspension on Day 1 with 
possible up-titration to 0.3 mg/kg and 0.6 mg/kg doses.

Subjects > 6 years of age and weighing 20 to 50 kg, inclusive, will receive a 
7.5 mg tablet on Day 1 with possible up-titration to 15-mg and 30-mg doses.

Subjects > 6 years of age and weighing > 50 kg, will receive a 15 mg tablet on 
Day 1 with possible up-titration to 30-mg and 60-mg doses.
Following their initial tolvaptan dose in the trial, subjects will continue dosing according 
to the titration scheme (see Section 3.2.4), targeting a final serum sodium concentration 
between 135 and 140 mEq/L (mmol/L).  Titration guidelines are designed to achieve a 
change in serum sodium concentration of at least 4 to 8 mEq/L (mmol/L)/24 hours but 
not 
.
3.2.4
Titration Guidelines and Rescue Therapy
Initiation and titration of tolvaptan must occur in a hospital setting.  Up titration can only 
take place on Treatment Day 2 (or 2a).  Titration (up or down) may not occur within 
20 hours of the previous dose.  Up-titration is limited to no more than twice the previous 
dose.
The medical monitor should be contacted at any point if questions arise regarding 
titration or initiation of rescue therapy.  The rationale for any up- or down-titration of 
tolvaptan must be documented.  The evaluation of serum sodium levels, management of 
tolvaptan titration, and rescue therapy is described in Figure 3.2.4-1.


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Serum Sodium Increase
Upward dose titration is only allowed during Treatment Phase A on Days 2 and/or 2a
Dose maintenance, downward titration, or interruption, or rescue therapy may be indicated at any time 
during the trial
Assess 
Serum Sodium
↑ > 4 to ≤8 mEq/L/24h
and
≤140 mEq/L
↑> 8 mEq/L/24h
or
>140 mEq/L
↑≤4 mEq/L/24h
and
<135 mEq/L
Maintain dose
Interrupt dosing & 
Discuss with Medical Monitor
Titrate to next higher dose for 
body weight
↑ ≥ 
or
>145 mEq/L
Interrupt dosing &
Call Medical Monitor 
Immediately
Serum Sodium Decrease 
or
No  Change
Rescue therapy
= 
proceed to 
Follow-up Phase C
Worsening symptoms and/or Serum 
Sodium at or below baseline
Repeat STAT Serum 
Sodium, start rescue therapy
Asymptomatic and Serum Sodium ↓
≥4 mEq/L but above baseline
Consider rescue therapy
Asymptomatic and Serum Sodium ↓
≤ 3 mEq/L but above baseline
No action required.
Manage clinically
Figure 3.2.4-1 Titration and Rescue Therapy Scheme
1 mEq/L = 1 mmol/L.
Figure 3.2.4-1
Titration and Rescue Therapy Scheme 
3.2.4.1
Titration
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 


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(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 interruption, concomitant medication adjustment, 
fluid supplementation and/or withdrawal).

If serum sodium level increases by
 
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.
3.2.4.2
Rescue Therapy
Rescue therapy is defined as any treatment, eg, hypertonic saline, isotonic saline (with or 
without diuretic for purpose of increasing the serum sodium level), 
plasmapheresis/dialysis, demeclocycline, urea, lithium, or commercially available 
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.  
If at any point during the trial serum sodium levels or hyponatremia symptoms worsen or 
fail to improve adequately and definitive therapy (eg, isotonic or hypertonic saline) is 
required, the subject will be withdrawn from trial treatment to receive rescue therapy
Please see Section 4.2 for further details. These subjects will continue to Follow-up 
Phase C for collection of safety information. 
Additional guidelines for rescue therapy concerning hyponatremia symptoms and 
decreasing serum sodium level:

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
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.


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Subjects who are randomized to the Early Withdrawal group will initially be observed to 
determine whether additional intervention is required to maintain appropriate serum 
sodium levels.  For those subjects whose serum sodium declines by 4 mEq/L (mmol/L) 
or whose overall clinical condition requires further treatment to increase serum sodium,
the investigator may consider rescue therapy per local standard of care.  Any intervention 
intended to raise serum sodium level during the first 48 hours in the responder Early 
Withdrawal group (including fluid restriction) will be defined as rescue therapy.  These 
subjects will be considered to have reached their clinical endpoint, and their data will be 
censored from that time forward.
Subjects randomized to the Late Withdrawal group who receive rescue therapy will be 
considered treatment failures.  A subject requiring rescue therapy at any time after 
starting tolvaptan will be discontinued from trial treatment and will proceed to Follow-up 
Phase C.
3.2.4.3
Fluid Restriction Considerations
In subjects with chronic hyponatremia, fluid restriction coadministered with initiation of 
treatment with a vaptan has the potential to accentuate the rate of sodium correction and 
to cause overly rapid correction or over correction of hyponatremia.  Therefore, during 
treatment, subjects must have access to water and maintain fluid intake levels per 
institutional guidelines.  Fluid restriction at any time during the trial including during the 
first 48 hours after discontinuation of tolvaptan will be considered rescue therapy.
3.3
Trial Population
This trial will include approximately 100 male and female subjects aged 4 weeks (or 
44 weeks adjusted gestational age) to < 18 years who have been diagnosed with 
euvolemic or hypervolemic hyponatremia (< 130 mEq/L [mmol/L]) that persists despite 
initial standard background therapy (including fluid restriction and excluding a 
vasopressin antagonist).  Age groups will be enrolled such that at least 50% of these 
subjects will be < 10 years old and at least 25% of subjects < 6 years old.  Subjects who 
are defined as responders will be further stratified by the magnitude of serum sodium 
response to tolvaptan (7 and > 7 mEq/L [mmol/L]), age, and underlying etiology of 
hyponatremia.
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


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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.24
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;25,26,27 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 
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.24,25
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.  
Sorbitol is metabolized to fructose.28  Subjects who have hereditary fructose intolerance 
(HFI) who continue to ingest fructose containing products can develop hepatic and renal 


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dysfunction.29  The tolvaptan suspension formulation contains sorbitol. Therefore, 
children who have HFI should not take the tolvaptan suspension formulation.
Hereditary fructose intolerance is typically diagnosed in young children upon the 
introduction of solid foods containing fructose, sucrose and/or sorbitol (eg, fruits and 
vegetables). It is not commonly diagnosed in children who are fed exclusively on breast 
milk. Clinical symptoms can include vomiting, nausea, restlessness, pallor, sweating, 
lethargy, coagulation disturbances and in some cases, apathy, coma, and convulsions.
Laboratory abnormalities may include signs of acute liver failure (eg, elevated serum 
transaminases, hyperbilirubinemia, abnormal blood clotting factors) or renal failure (eg,
proteinuria, generalized hyperaminoaciduria, metabolic acidosis). Continued exposure to 
fructose can result in hypoglycemia, hepatomegaly, jaundice, steatosis, coagulation 
disturbances, edema, ascites and signs of proximal renal tubular dysfunction. If HFI is 
suspected, a thorough history that emphasizes nutritional complaints including the timing 
of the introduction of fruits and vegetables to the diet should be obtained as well as the 
appropriate laboratory assessment for confirmation of diagnosis.29
For children aged > 2 years, a detailed history with regard to HFI symptoms has to be 
taken prior to trial entry.
3.3.1
Subject Eligibility by Hyponatremia Etiology
3.3.1.1
General Guidelines
Investigators should assess subjects’ appropriateness to receive tolvaptan.  Investigators
should ultimately use their medical judgment to make the final determination. It remains 
the responsibility of the investigator to determine the etiology of hyponatremia and to 
assess the volume status for each subject using diagnostic tests (eg, fractional excretion of 
sodium [FENa], fractional excretion of urea [FE urea], urine osmolality, serum
osmolality) employed in the usual clinical course of care.
3.3.1.2
Specific Guidelines by Etiology

Subjects diagnosed with hyponatremia secondary to SIADH will be evaluated 
specifically to ensure appropriate volume status.  Hypovolemic states are not 
compatible with tolvaptan administration.  Plasma and urine sodium, potassium, 
creatinine, and urea should be assessed in order to calculate and evaluate FENa
and FE urea prior to dosing to ensure safety of tolvaptan administration.

For hyponatremia due to hepatocellular disease (including cirrhosis), in addition 
to the above guidelines, the underlying etiology of hepatocellular disease must be 
documented.  

For hyponatremia due to HF:  
1) A definitive diagnosis of HF by a cardiologist must be documented.  


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2) 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.  At 
least 1 day or a minimum of 3 half-lives are required for washout.
The medical monitor should be contacted if there are questions.  The guidelines listed in 
Table 3.3.1.2-1 are to help guide the medical judgment of the investigator.
Table 3.3.1.2-1
Screening Algorithms by Hyponatremia Etiology
Etiology
Instruction
All etiologies
Two documented serum sodium assessments of < 130 mEq/L (mmol/L) at least 
12 hours apart
One serum sodium assessment of < 130 mEq/L (mmol/L) within 2-4 hours prior 
to tolvaptan administration
Screen subjects for AKI criteria per exclusion criteria
Collect labsa
Calculate serum osmolality, FENa, and FE urea at pretreatment baseline only
HF
Cardiologist documented diagnosis of HF
Discontinue or stabilize diuretic use prior to tolvaptan administration
Hepatocellular disease 
(including cirrhosis)
The underlying etiology of hepatocellular disease must be documented
AKI = acute kidney injury.
aRefer to Table 3.7.4.2.3-1 for complete lists of laboratory assessments.
3.4
Eligibility Criteria
3.4.1
Informed Consent/Assent
Written informed consent and assent, as appropriate, will be freely obtained from the 
subject’s parent/legal guardian or legally acceptable representative, 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 screening 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 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 


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Practice (GCP) Guideline30 and local regulatory requirements.  The investigator will 
review any written 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).
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject and his/her parent/legal guardian or legally acceptable 
representative by the investigator (or a qualified designee), the IRB/IEC-approved written 
ICF will be signed and dated by both the subject’s parent/legal guardian or legally 
acceptable representative 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 informed assent by signing the appropriate 
form for their age group.  The subject’s parent/legal guardian or legally acceptable 
representative 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/legal guardian(s) or legally acceptable representative(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.


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3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
1.
Male and female subjects 4 weeks (or 44 weeks adjusted gestational age) to < 18 years old
2.
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
3.
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 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 final trial qualification and clinical management strategy, is to be 
obtained within 2-4 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/legal 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 Screening 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 
IMP for sexually active females of childbearing potential
IMP = investigational medicinal product.
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
1.
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.
Current use or expected use during the trial of a potent CYP3A4 inhibitor in subjects weighing 
< 12 kg or a moderate CYP3A4 inhibitor in subjects weighing < 6 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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Table 3.4.3-1
Exclusion Criteria
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 Screening 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.
Subjects who have cirrhosis and meet 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 another investigational drug trial within the past 30 days, without prior approval 
from the sponsor medical monitor
25.
Subjects who weigh < 3 kg
26.
Unable to swallow tablets if the suspension formulation is unavailable
27.
Subjects who require the suspension formulation and have Hereditary Fructose Intolerance
eGFR = estimated glomerular filtration rate; ICU = intensive care unit.
Use of the suspension formulation is at the discretion of the local regulatory authorities 
and IRB/IECs.


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3.5
Outcome Variables
3.5.1
Primary Efficacy Outcome Variable
For subjects with serum sodium level increases of 4 mEq/L (mmol/L) (ie, responders), 
change in serum sodium concentration from Day 2 (or 2a) at the end of Treatment 
Phase A to the end of Treatment Phase B for Early compared to Late Withdrawal groups.
3.5.2
Key Secondary Efficacy Outcome Variable
For all subjects, the key secondary endpoint is the change in serum sodium concentration 
at the end of Day 2 (or 2a) in Treatment Phase A from baseline. 
3.5.3
Other Secondary Outcome Variables
3.5.3.1
Safety Variables
The safety endpoints for all subjects include:

Percentage of subjects with overly rapid increase in serum sodium level 
)

Change in serum sodium level from 24 hours post-last dose to 7 days post-last 
dose

Percentage of subjects requiring rescue therapy (other than fluid restriction)
during Treatment Phase A and Treatment Phase B 

Percentage of subjects requiring fluid restriction during Treatment Phase A and 
Treatment Phase B 

Vital signs, blood pressure, clinical laboratory tests, body weight, and 
neurological examinations
3.5.3.2
Pharmacokinetic Variables
Pharmacokinetic endpoints are tolvaptan Cmax, time to maximum (peak) plasma 
concentration (tmax), and AUC from time zero to 24 hours (AUC0-24h) on Day 1.
3.5.3.3
Pharmacodynamic Variables
Pharmacodynamic endpoints are fluid intake, urine output, and fluid balance 
(intake minus output) every 6 hours on Days 1 and 2 in Treatment Phase A.
3.5.4
Exploratory Variables

Efficacy will be assessed in nonresponders continuing on tolvaptan therapy by 
change from baseline in serum sodium concentration at the end of Treatment 
Phase B compared to the end of Treatment Phase A


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
In all subjects, 24-hour excretion of sodium, creatinine, and urine osmolality on 
Days 1 and 2

24-hour sodium clearance on Day 1

Quality of life (QoL) assessments
3.6
Measures to Minimize/Avoid Bias
This is an open-label trial.  Subjects defined as responders from Treatment Phase A will 
be randomized to either the Early Withdrawal group or the Late Withdrawal group in 
Treatment Phase B.  Treatment assignments for Treatment Phase B will be based on a 
computer-generated randomization code provided by Otsuka Pharmaceutical 
Development & Commercialization, Inc. (OPDC) Biometrics Department.
3.7
Trial Procedures
Treatment in this trial will last up to 5 days.  Any initiation or titration of tolvaptan must 
occur in a hospital setting.  Parent(s)/legal guardian(s) or legally acceptable 
representative(s) must provide informed consent and subjects must provide informed
assent (as appropriate) and be screened 1 or 2 days prior to dosing.
In Treatment Phase A, subjects who meet the inclusion and exclusion criteria will be 
enrolled and will be administered tolvaptan doses based on age, weight, ability to 
swallow a tablet, and the use of CYP3A4 inhibitors.  At the end of Day 2 (or 2a) in 
Treatment Phase A, subjects who are responders will be randomized to either continue 
treatment with tolvaptan for 2 additional days (Late Withdrawal) or to discontinue 
tolvaptan treatment (Early Withdrawal).
In Treatment Phase B, subjects who are nonresponders may continue on tolvaptan 
therapy for 2 additional days or may be withdrawn from tolvaptan to be treated per the 
investigator’s preferred standard of care.  During Treatment Phase B, subjects in the Late 
Withdrawal group and nonresponders continuing treatment will continue to receive
tolvaptan for 2 additional days and all subjects will have serum sodium levels measured 
at 12 (4) hours postdose and at trough (24 [4] hours post-previous dose) each day.  
Subjects in the Early Withdrawal group should be monitored for the first 48 hours post-
last dose.
In Follow-up Phase C, all subjects will be monitored and will have an additional serum 
sodium measurement at 72 (4) hours post-last dose as well as at 7 (+ 1) days post-last 
dose.  A final safety follow-up telephone contact/visit will be performed 14 (+ 2) days 
post-last dose.


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Trial assessment time points are summarized in Table 3.7-1.  Section 3.7.1 provides a 
flow overview that describes the sequence of assessments during a visit.  Section 3.7.2
provides details around efficacy assessments, Section 3.7.3 provides details around 
pharmacokinetic/pharmacodynamic assessments and Section 3.7.4 provides details 
around safety assessments.
Pharmacokinetic samples will be obtained for all subjects on Day 1 at 2 and 8 hours 
post-first dose and at trough (24 [4] hours post-previous dose) on Days 1, 2, 3, and 4
for all subjects dosed with tolvaptan on Days 1, 2, 3, and 4, respectively, regardless of 
responder status.  Once adequate PK data are obtained, PK sampling will be discontinued 
for all subjects.
Subjects will be required to be in a hospital setting during initiation or titration of 
tolvaptan.  A subject is allowed to be discharged, if they:
1) Continue to come to the clinic for daily study assessments and
2) Are either:
a) A nonresponder on standard of care or 
b) On a stable dose of study drug, or 
c) In the early withdrawal group without study treatment.  
Follow-up for all subjects 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.


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Table 3.7-1
Schedule of Assessments
Procedures
Screening
Treatment Phase A
Treatment Phase B
Follow-up Phase C
Day -2 to 
-1
Day 1
Day 2
Day 2a 
(optional)
Day 3
Day 4
Day 5a
72 (4) h 
post last 
dose
7 (+1) 
days post-
last dose
14 (+2) 
days post-
last dose
Early 
Termin-
ation (ET)
Informed Consent/Assent
X
Inclusion/exclusion 
criteriab
X
X
Demographic information
X
Medical and 
hyponatremia history
X
Vital signsc
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
Heightd
X
Body weightd,e
X
X
X
X
X
X
X
X
X
X
Physical examinationf
X
X
X
X
X
X
X
X
X
Tanner staging
X
Neurological examination
X
Xg
X
X
X
X
X
X
Clinical status 
assessmenth
X
X
X
X
X
X
X
X
X
Quality of life assessment
X
X
X
Alcohol/drug screeni
X
Pregnancy test (if 
applicable)j
X
X
Fluid intakek
X
X
Urine volumel
X
X
Urinalysis
X
X
X
Urine chemistryk,l
X
X
X
Serum sodiumm
X
X
X
X
X
X
X
X
X


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Table 3.7-1
Schedule of Assessments
Procedures
Screening
Treatment Phase A
Treatment Phase B
Follow-up Phase C
Day -2 to 
-1
Day 1
Day 2
Day 2a 
(optional)
Day 3
Day 4
Day 5a
72 (4) h 
post last 
dose
7 (+1) 
days post-
last dose
14 (+2) 
days post-
last dose
Early 
Termin-
ation (ET)
Hematology, coagulation, 
and serum chemistryn
X
X
X
Serum osmolality, FENa, 
and FE urea
X
TSH and cortisolo
X
PK plasma samplesp
X
X
X
X
X
Tolvaptan dosingq
X
X
X
X
X
Swallow test
Xr
Assessment for response 
to tolvaptan
X
X
Palatability and 
acceptability assessment
X
Randomization
X
Follow-up phone call or 
visit
X
Vital statuss
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; eCRF = electronic case report form; TSH = thyroid-stimulating hormone.
aThe Day 5 visit is only for Late Withdrawal subjects and nonresponders continuing on tolvaptan treatment.
bInclusion/exclusion criteria will be checked at screening and predose on Day 1.
cVital signs (blood pressure, heart rate, respiratory rate, and temperature) will be assessed after the subject has been supine for 3 minutes and prior to any 
blood draws.  Vital signs are to be assessed at 4 hours and 8 hours postdose on Day 1 and, on Days 2 through 4, at trough (24 [± 4] hours post-previous 
dose, but prior to the next dose).
dRecord growth percentiles at screening only.
eWeight will be taken predose.


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fThe initial physical examination should be a full physical.  Subsequent physical examinations can be directed physical examinations that are focused on 
hyponatremia-related signs and symptoms as well as any major changes from baseline.  A physical examination should include a fontanelle assessment as 
age appropriate.
gA neurological examination will be performed predose and at 8 hours post-first dose.
hClinical status assessment must be performed predose on Day 1.  It is preferred that clinical status assessments be performed predose during subsequent visits.  
Clinical status assessments will be performed per inpatient standard of care, ie, review subject chart entries (including hyponatremia assessment notes and 
laboratory results [trial and nontrial specific], any examination findings, medical problem list changes, and fluid intake and output) to evaluate overall subject 
eligibility in terms of hyponatremia state.  Volume status will be assessed every 6 hours prior to trial entry and every 6 hours during Treatment Phase A.
iAlcohol/drug screen is performed per clinical judgment and institutional guidelines.
jA serum or urine pregnancy test will be performed on female subjects 12 years of age and all female subjects < 12 years of age if menstruation has started.  
In the case of a positive urine pregnancy test result, a serum pregnancy test will be performed as confirmatory.
kIntervals starting immediately after dosing at Hour 0 (0-6, 6-12, 12-18, and 18-24 hours).
lSamples within a collection interval are to be refrigerated and pooled.  An aliquot for urine chemistry tests will be taken for each collection interval.  Urine 
urea is to be measured at screening only.
mSerum sodium assessments are closely tied to dosing time points and PK blood draws.

Screening: 2 assessments should be taken, at least 12 hours apart (may be part of medical history).  One assessment can be combined with the 
serum chemistry panel.

Treatment Phase A: Baseline (STAT) assessment will be within 2-4 hours prior to first dose.  Post-first dose assessments: 8 (-1 to + 0.25) hours and 
trough (24 [± 4] hours postdose [STAT assessment]).  Then every 12 (± 4) hours thereafter (alternating 12 hours postdose and at trough [24 (± 4) 
hours postdose; STAT assessment])

Treatment Phase B: Assessments to be taken every 12 (± 4) hours (alternating 12 hours postdose and at trough [24 (± 4) hours postdose; STAT 
assessment])

Treatment Phase C: Assessments to be taken at 72 (± 4) hours post-last dose (can be combined with the serum chemistry panel) and at the 7 (+1) 
days post-last dose visit.
In addition to serum sodium samples obtained for trial 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 (± 1) hours postdose, and on 
Day 2 (and Day 2a, if applicable) at 6 (-1 to + 0.25) hours postdose as well as at 18 (± 1) hours postdose.  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).
nSerum chemistry panel includes serum sodium and assessments can be combined for visits where both assessments are indicated.
oResults of these tests will further characterize hyponatremia etiology for the Hyponatremia History eCRF and are not required to determine eligibility.  
Subjects who have clinically relevant TSH or cortisol levels may not respond properly to tolvaptan and will be withdrawn from the trial.


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pPK samples are closely tied to dosing time points and serum sodium assessments.  An early termination (ET) sample will be taken for any subject who is 
receiving tolvaptan.

In Treatment Phase A, PK samples should be collected on Day 1 at 2 hours (5 minutes) and 8 hours post-first dose and assessed at trough (24 [
4] hours post-first dose). A PK sample should be assessed on Day 2 at trough (24 [4] hours post-previous dose, but prior to the next dose).  On 
Day 2a no PK samples are taken.

In Treatment Phase B, PK will be assessed in subjects continuing treatment with tolvaptan (Late Withdrawal group and nonresponders continuing 
on tolvaptan) at trough (24 [± 4] hours post-previous dose, but prior to the next dose) on Days 3 and 4.
If there are restrictions in the allowable total daily blood volumes per local guidelines and subject age, the PK assessment schedule should be the following:

Day 1at 2 hours postdose (5 minutes)

Day 2 at 8 (2) hours postdose (may be concurrent with serum sodium or other blood sampling)

Days 3 and 4 at trough (24 [± 4] hours post-previous dose, but prior to the next dose and concurrent with serum sodium sample)
qThe tolvaptan dose will be titrated based on serum sodium levels as described in Section 3.2.4.
rOptional swallow test for subjects for whom it is unknown if they are able to swallow tablets, at the investigator’s discretion.
sVital status will be collected at 14 days post-last dose only for subjects who discontinued early and did not withdraw consent.  


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3.7.1
Schedule of Assessments
3.7.1.1
Screening
The procedures listed below will be performed during the Screening Visit (Days −2 
to −1) to ensure that 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.
a) Informed consent will be obtained from each subject’s parent/legal guardian
or legally acceptable representative prior to any trial procedures being 
conducted.
b) Each subject who is able will indicate willingness to participate in the trial by 
signing or marking an assent form (as applicable) supplied for this purpose.
2) Inclusion and exclusion criteria will be reviewed.
3) Demographic information will be collected.
4) Medical and hyponatremia history will be recorded.  
a) Medical history should include the subject’s current list of medical problems
that impacts the subject’s current hospital stay.  
b) The hyponatremia medical history should include the etiology of subject’s 
hyponatremia (see Section 3.3.1) and what treatment was administered prior 
to trial enrollment.  A detailed history specific to etiology of hyponatremia 
will also be recorded.
c) Any observable symptoms of hyponatremia will be assessed and recorded.
5) 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.
6) A resting 12-lead electrocardiogram (ECG) will be performed after the subject 
has been supine and at rest 10 minutes.
7) Body height and weight will be measured.  Growth percentiles will be recorded.
8) The initial physical examination should be a full physical.  Subsequent physical 
examinations can be directed physical examinations that are focused on 
hyponatremia-related signs and symptoms as well as any major changes from 
baseline.
9) Tanner staging will be performed. 
10) A neurological examination will be performed.
11) Quality-of-life (QoL) assessment will be performed, as appropriate by age and 
where available.
12) Clinical status assessments will be performed per inpatient standard of care, eg, 
subject chart entries will be reviewed (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], any examination findings, 


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medical problem list changes, and fluid intake and output) to evaluate the 
subject’s hyponatremia state.
13) Alcohol/drug screen is performed per clinical judgment and institutional 
guidelines.
14) A serum or urine pregnancy test will be performed on all female subjects 
12 years of age and all female subjects < 12 years of age if menstruation has 
started.  In the case of a positive urine pregnancy test result, a serum pregnancy 
test will be performed as confirmatory.
15) Urinalysis and urine chemistry laboratory samples will be collected for analysis. 
16) Two blood samples for serum sodium testing will be collected at least 12 hours 
apart and can be part of the recent medical history to document chronic 
hyponatremia.  (One of these blood draws can be combined with the serum 
chemistry panel as appropriate to minimize blood draws.)
17) Hematology, coagulation, and serum chemistry laboratory samples will be 
collected for analysis.
18) Serum osmolality, FENa, and FE urea will be calculated.
19) Thyroid-stimulating hormone (TSH) and cortisol blood samples will be collected 
to determine possible need for alternate mode of therapy.
20) Concomitant medications will be recorded.
21) Adverse events will be recorded.
22) Optional swallow test for subjects for whom it is unknown if they are able to 
swallow tablets, at the investigator’s discretion.  Placebo tablets will be provided 
for use in performing this test at screening.
3.7.1.2
Treatment Phase A
During Treatment Phase A every effort should be made to have accurate dosing time 
points and follow the sequence of assessments specified below as PK/PD assessments 
and serum sodium blood draws are closely tied to dosing time points.
3.7.1.2.1
Day 1
The procedures listed below will be performed on Day 1 for all subjects.  
Predose
1) Any observable symptoms of hyponatremia will be assessed within 2 hours prior 
to first dose to confirm eligibility as part of a clinical status assessment.  Clinical 
status assessments will be performed per inpatient standard of care, eg, subject
chart entries will be reviewed (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], any examination findings, 
medical problem list changes, and fluid intake and output) to evaluate the 
subject’s hyponatremia state.


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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 
assessed prior to blood draws.
3) A blood sample for STAT serum sodium testing will be collected within 2 to 
4 hours prior to dosing.  
4) Body weight will be measured.
5) A directed physical examination will be performed.
6) A neurological examination will be performed.
7) Inclusion and exclusion criteria will be reviewed and confirmed.
Dosing
8) Tolvaptan will be administered.
Postdose
9) A blood sample will be collected at 2 hours (5 minutes) post-first dose for PK 
analysis of tolvaptan (central laboratory).
10) Vital signs will be assessed at 4 and 8 hours post-first dose.  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 at 
8 hours.
11) Fluid intake will be recorded at 6-hour intervals starting at Hour 0 (0-6, 6-12, 
12-18, and 18-24 hours).
12) Urine will be collected at 6-hour intervals starting at Hour 0 (0-6, 6-12, 12-18, 
and 18-24 hours).  Subjects should be asked to void just prior to the end time of 
each collection interval, as possible. 
a) Urine volume will be determined from urine voids made during the 6-hour 
collection intervals which will be pooled prior to determination of final 
volume.
b) A urine chemistry sample will be collected and assessed from each 6-hour 
volume interval starting at Hour 0 (0-6, 6-12, 12-18, and 18-24 hours).
13) Blood samples will be collected concurrently at 8 hours (-1 to + 0.25) post-first 
dose for:
a) Serum sodium testing 
b) PK analysis
14) A neurological examination will be performed at 8 hours post-first dose.
15) 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 (± 1) hours postdose.  This 
sodium safety assessment will be repeated at 6 (-1 to + 0.25) and 18 (± 1) 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).


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16) Blood samples will be collected concurrently at trough (24 [4] hours post-first 
dose) for:
a) A blood sample for STAT serum sodium testing should be taken and the 
results known prior to subsequent tolvaptan dosing. 
b) A blood sample for PK analysis.
Throughout the visit
17) Concomitant medications will be recorded.
18) Adverse events will be assessed.
3.7.1.2.2
Day 2
The following procedures will be performed on Day 2 for all subjects.  
Trough (24 [± 4] hours post-first dose)
1) Vital signs will be assessed.  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 predose and prior to blood draws.
2) Clinical status assessments will be performed per inpatient standard of care, eg, 
subject chart entries will be reviewed (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], any examination findings, 
medical problem list changes, and fluid intake and output) to evaluate the 
subject’s hyponatremia state.
3) Complete fluid intake and urine volume collection for specified intervals prior to 
next dosing with tolvaptan.
4) A directed physical examination will be performed.
5) Body weight will be measured.
6) A neurological examination will be performed.
Dosing
7) Tolvaptan will be administered.
If the subject’s serum sodium concentration is < 135 mEq/L (mmol/L) and a 
4 mEq/L (mmol/L) increase, tolvaptan dose should be adjusted per the titration 
guidelines (Section 3.2.4) for the assigned weight group.
Postdose
7) Assess palatability and acceptability of the tolvaptan dose for subjects 
immediately after dosing and again between 15 to 20 minutes after dosing.
8) Fluid intake will be recorded at 6-hour intervals starting at Hour 0 (0-6, 6-12, 12-
18, and 18-24 hours).
9) Urine will be collected at 6-hour intervals starting at Hour 0 (0-6, 6-12, 12-18, 
and 18-24 hours).  Subjects should be asked to void just prior to the end time of 
each collection interval, as possible. 


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a) Urine volume will be determined from urine voids made during the 6-hour 
collection intervals which will be pooled prior to determination of final 
volume.
b) A urine chemistry sample will be collected and assessed from each 6-hour 
volume interval starting at Hour 0 (0-6, 6-12, 12-18, and 18-24 hours).
10) A blood sample will be collected for serum sodium testing at 12 (± 4) hours 
postdose.
12) 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.  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).
13) At the end of the Day 2 visit subjects will be assessed for response to tolvaptan 
treatment.  Subjects who are:
a) Responders (serum sodium level increase of 4 mEq/L [mmol/L]) will 
proceed to Treatment Phase B (see Section 3.7.1.3) for randomization.
b) Not responding to tolvaptan treatment (serum sodium level increase of 
< 4 mEq/L [mmol/L]) will proceed to Day 2a (see Section 3.7.1.2.3).
14) Blood samples will be collected concurrently at trough (24 [4] hours post-
previous dose) for:
a) STAT serum sodium testing and the results known prior to subsequent 
tolvaptan dosing. 
b) PK analysis of tolvaptan.
Throughout the visit
15) Concomitant medications will be recorded.
16) Adverse events will be assessed.
3.7.1.2.3
Day 2a (optional)
The following procedures will be performed on Day 2a for all subjects who are not 
responsive to tolvaptan treatment at the end of Day 2.  
Trough (24 [± 4] hours post-previous dose)
1) Vital signs will be assessed at 24 hours post-previous dose.  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 predose and prior to 
blood draws.
2) Clinical status assessments will be performed per inpatient standard of care, eg, 
subject chart entries will be reviewed (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], any examination findings, 


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medical problem list changes, and fluid intake and output) to evaluate the 
subject’s hyponatremia state.
Predose
3) A directed physical examination will be performed.
4) Body weight will be measured.
Dosing
5) Tolvaptan will be administered.
If the subject’s serum sodium concentration is < 135 mEq/L (mmol/L) and a 
4 mEq/L (mmol/L) increase, tolvaptan dose should be adjusted per the titration 
guidelines (Section 3.2.4) for the assigned weight group.
Postdose
6) A blood sample will be collected for serum sodium testing at 12 (± 4) hours 
postdose.
7) 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.  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).
8) At the end of the Day 2a visit subjects will be assessed for response to tolvaptan 
treatment.  Subjects who are:
a) Responders (serum sodium level increase of 4 mEq/L [mmol/L]) will 
proceed to Treatment Phase B (see Section 3.7.1.3) for randomization.
b) Nonresponders (serum sodium level increase of < 4 mEq/L [mmol/L]) will 
continue to Treatment Phase B where they either continue on tolvaptan 
therapy for 2 additional days or are withdrawn from tolvaptan to be treated per 
the investigator’s preferred standard of care.
9) A blood sample will be collected for serum sodium testing at trough 
(24 [± 4] hours postdose).
Throughout the visit
10) Concomitant medications will be recorded.
11) Adverse events will be assessed.


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3.7.1.3
Treatment Phase B
3.7.1.3.1
Day 3
The following procedures will be performed on Day 3.  Some assessments are required 
for all subjects while other assessments only apply to certain subsets of subjects as 
indicated.
For all subjects
At trough (24 [± 4] hours post-previous dose) the following assessments will be 
performed:
1) Vital signs will be assessed.  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 predose and prior to blood draws.
2) Clinical status assessments will be performed per inpatient standard of care, eg, 
subject chart entries will be reviewed (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], any examination findings, 
medical problem list changes, and fluid intake and output) to evaluate the 
subject’s hyponatremia state.
For all subjects classified as Responders at the end of Treatment Phase A
1) Randomize the subject to the Early or Late Withdrawal group using the trial’s 
interactive web response system (IWRS).
For subjects receiving tolvaptan (Late Withdrawal group and nonresponders with 
continuing treatment)
1) Body weight will be measured predose.
2) A directed physical examination will be performed predose.
3) A neurological examination will be performed.
4) Tolvaptan will be administered.
5) A blood sample will be collected for serum sodium testing at 12 (± 4) hours 
postdose.
6) Blood samples will be collected concurrently at trough (24 [4] hours post-
previous dose) for:
a) STAT serum sodium testing and the results known prior to subsequent 
tolvaptan dosing. 
b) PK analysis of tolvaptan.
8) Concomitant medications will be recorded.
9) Adverse events will be assessed.


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For subjects not receiving tolvaptan treatment (Early Withdrawal group and 
nonresponders treated with standard of care)
1) Early Withdrawal subjects will be observed to determine whether additional 
intervention is required to maintain appropriate serum sodium levels.
2) Nonresponders discontinuing tolvaptan will be treated per the investigator’s 
preferred standard of care.
3) A directed physical examination will be performed.
4) A neurological examination will be performed.
5) A blood sample will be collected for serum sodium testing at 12 (± 4) hours post 
the nominal dosing time.
6) A blood sample will be collected for serum sodium testing at 24 (± 4) hours post 
the nominal dosing time.
7) Concomitant medications will be recorded.
8) Adverse events will be assessed.
3.7.1.3.2
Day 4
The following procedures will be performed on Day 4.  Some assessments are required 
for all subjects while other assessments only apply to certain subsets of subjects as 
indicated.
For all subjects 
At trough (24 [± 4] hours post-previous dose) the following assessments will be 
performed:
1) Vital signs will be assessed.  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 predose and prior to blood draws.
2) Clinical status assessments will be performed per inpatient standard of care, eg, 
subject chart entries will be reviewed (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], any examination findings, 
medical problem list changes, and fluid intake and output) to evaluate the 
subject’s hyponatremia state.
For subjects receiving tolvaptan (Late Withdrawal group and nonresponders with 
continuing treatment)
1) Body weight will be measured predose.
2) A directed physical examination will be performed predose.
3) A neurological examination will be performed.
4) Tolvaptan will be administered.


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5) A blood sample will be collected for serum sodium testing at 12 (± 4) hours 
postdose.
6) A QoL assessment will be conducted.
7) Blood samples will be collected concurrently at trough (24 [4] hours post-
previous dose) for:
a) STAT serum sodium testing and the results known prior to subsequent 
tolvaptan dosing.
b) PK analysis of tolvaptan.
8) Concomitant medications will be recorded.
9) Adverse events will be assessed.
For subjects not receiving tolvaptan treatment (Early Withdrawal group and 
nonresponders treated with standard of care)
1) Early Withdrawal subjects will be observed to determine whether additional 
intervention is required to maintain appropriate serum sodium levels.
2) Nonresponders discontinuing tolvaptan will continue to be treated per the 
investigator’s preferred standard of care.
3) A directed physical examination will be performed.
4) A neurological examination will be performed.
5) A blood sample will be collected for serum sodium testing at 12 (± 4) hours post 
the nominal dosing time.
6) A QoL assessment will be conducted.
7) Concomitant medications will be recorded.
8) Adverse events will be assessed.
3.7.1.3.3
Day 5
The following procedures will be performed on Day 5.  
For subjects receiving tolvaptan (Late Withdrawal group and nonresponders with 
continuing tolvaptan treatment)
At trough (24 [4] hours post-previous dose)
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 
performed prior to blood draws.
2) Body weight will be measured.
Throughout the visit
3) Concomitant medications will be recorded.


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4) Adverse events will be assessed.
For subjects not receiving tolvaptan treatment (Early Withdrawal group and 
nonresponders treated with standard of care)
1) Proceed to Follow-up Phase C, as for these subjects the 72-hour post-last dose 
time point (Section 3.7.1.4.1) falls on the morning of Day 5.
3.7.1.4
Follow-up Phase C
3.7.1.4.1
72 Hours Post-last Dose or ET
The following procedures will be performed for all subjects at 72 (4) hours post-last 
dose or at early termination (ET).  
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 
performed prior to blood draws.
2) Hematology, coagulation, and serum chemistry laboratory samples will be 
collected.
3) For Early Termination only: 
Blood sample for PK analysis of tolvaptan will be collected for all subjects on 
tolvaptan.  The sample is to be taken concurrently with the serum sodium sample 
(part of the serum chemistry panel).  
4) A directed physical examination will be performed.
5) A neurological examination will be performed.
6) Body weight will be measured.
7) A urinalysis laboratory sample will be collected.
8) Clinical status assessments will be performed per inpatient standard of care, eg, 
subject chart entries will be reviewed (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], any examination findings, 
medical problem list changes, and fluid intake and output) to evaluate the 
subject’s hyponatremia state.
9) For Early Termination: 
Subjects will be monitored and treated as clinically warranted per the 
investigator’s preferred standard of care for up to 3 additional days after the last 
dose of tolvaptan.
10) Concomitant medications will be recorded.
11) Adverse events will be assessed.
12) If a subject terminates early from the trial and agrees to continued telephone 
contact, the subject or parent/legal guardian or legally acceptable representative 
will be contacted by telephone at 14 days post-last dose for vital status.


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3.7.1.4.2
7 Days Post-last Dose
Subjects will be assessed for maintenance of normal or target serum sodium 
concentration at 7 (+ 1) days post-last dose. All clinical labs will be performed locally.  
If the subject was discharged, he/she should return to the clinic for this 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 
performed prior to blood draws.
2) A blood sample for serum sodium testing will be collected.
3) A serum or urine pregnancy test will be performed on all female subjects 
12 years of age and all female subjects < 12 years of age if menstruation has 
started.  In the case of a positive urine pregnancy test result, a serum pregnancy 
test will be performed as confirmatory.
4) A QoL assessment will be conducted.
5) A directed physical examination will be performed.
6) A neurological examination will be performed.
7) Clinical status assessments will be performed per inpatient standard of care, eg, 
subject chart entries will be reviewed (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], any examination findings, 
medical problem list changes, and fluid intake and output) to evaluate the 
subject’s hyponatremia state.
8) Body weight will be measured.
9) Concomitant medications will be recorded.
10) Adverse events will be assessed.
3.7.1.4.3
14 Days Post-last Dose
Subjects or their parent(s)/legal guardian(s) or legally acceptable representative(s) will be 
contacted via telephone or will be asked to come back to the clinic for a visit at
14 (+ 2) days post-last dose to assess any new or ongoing AEs and to collect information 
on any medications administered since the last visit.  Ongoing follow-up may be required 
after a subject’s trial completion for health status before the analysis of all trial results is 
completed.
3.7.2
Efficacy Assessments
Efficacy will be assessed through determination of overall serum sodium concentrations 
and clinical status assessments.


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3.7.2.1
Serum Sodium Concentrations
Monitoring frequency of serum sodium is at the discretion of the clinical investigator; 
however, the minimum sample collection required for all subjects is described in 
Section 3.7.1 and Section 3.7.4.2.1.
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).
In order to qualify for this trial, subjects must have documentation of chronic dilutional 
hyponatremia (serum sodium < 130 mEq/L [mmol/L]) that is present for ≥48 hours.  
Specifically, each subject must have 2 blood samples collected at least 12 hours apart 
over a minimum of 48 hours for assessment of baseline serum sodium level to determine 
subject eligibility.  These can be either part of the recent medical history concerning the 
current hospital stay or prospectively collected as part of this trial.
On Day 1, a third (STAT) serum sodium sample should be drawn within 2-4 hours prior 
to dosing; the results must be verified to be < 130 mmol/L prior to the first dose.  Serum 
sodium assessments should be performed at 8 hours post-first dose and at trough 
(24 [±4] hours post-first dose; this assessment will fall on Day 2 predose). 
On Day 2 (or 2a), Day 3, and Day 4 (through the following morning on Day 5):

For all subjects receiving tolvaptan (Late Withdrawal and nonresponders 
continuing on tolvaptan) serum sodium assessments will be performed at trough 
(24 [±4] hours post-previous dose) and 12 (± 4) hours postdose each day during 
Treatment Phase A and Treatment Phase B.

For all subjects not receiving tolvaptan (Early Withdrawal and nonresponders 
treated with standard of care) serum sodium assessments will be performed every 
12 (± 4) hours throughout Treatment Phase A and Treatment Phase B.  
For all subjects final serum sodium assessments will be taken at 72 (± 4) hours post-last 
dose and 7 days post-last dose.
The serum sodium assessments schedule is presented in Table 3.7.2.1-1.


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Table 3.7.2.1-1
Serum Sodium Assessments
Blood Draws for Serum Sodium
Phase
Visit
Day
Efficacy
Supplemental Safety
Treatment 
Phase A
Screening
−2 to −1
2 blood samples, at least 
12 hours apart
-
Titration
1
Within 2 to 4 hours prior to 
dosing (STAT)
-
8 (-1 to + 0.25) hours 
post-first dose
4 to 6 hours postdose
24 (± 4) hours post-first 
dose (STAT)
18 (± 1) hours 
postdose
2
12 (± 4) hours postdose
6 (-1 to + 0.25) and 
18 (± 1) hours 
postdose
24 (± 4) hours post-previous 
dose (trough) (STAT)
-
2a 
(Optional)
12 (± 4) hours postdose
6 (-1 to + 0.25) and 
18 (± 1) hours 
postdose
24 (± 4) hours post-previous 
dose (trough) (STAT)
-
Treatment 
Phase B
Late Withdrawal 
group and 
nonresponders with 
continuing treatment
3
12 (± 4) hours postdose
-
24 (± 4) hours post-previous 
dose (trough) (STAT)
-
4
12 (± 4) hours postdose
-
24 (± 4) hours post-previous 
dose (trough)
-
Early Withdrawal 
group and 
nonresponders treated 
with standard of care
3
12 (± 4) hours post nominal 
dosing
-
24 (± 4) hours post nominal 
dosing
-
4
12 (± 4) hours post nominal 
dosing
-
Follow-up 
Phase C
Follow-up
-
72 (± 4) hours post-last dose
-
-
7 (+ 1) days post-last dose
-
3.7.2.2
Clinical Assessments
Clinical status assessment must be performed predose on Day 1.  It is preferred that 
clinical status assessments be performed predose during subsequent visits.  Clinical 
assessments will be performed per inpatient standard of care and should include review 
of subject 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 


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performed by a trial investigator who will be aware of laboratory and other clinical 
response data.
3.7.2.3
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, subject and parent/caregiver, 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 screening, Day 4 and 7 days post-last dose.
3.7.3
Pharmacokinetic/Pharmacodynamic Assessments
3.7.3.1
Pharmacokinetic Assessments
3.7.3.1.1
Blood Collection Times
Blood samples will be taken so that tolvaptan and metabolite concentrations can be 
determined.  Samples will be taken at the following times:

On Day 1 at 2 hours (5 minutes) and 8 hours (concurrent with 8 h serum sodium 
sample) post-first dose.  

On Days 1, 2, 3, and 4 samples will be taken at trough (24 [4] hours 
post-previous dose) (prior to the subsequent dose), concurrent with serum sodium 
samples,  for subjects dosed with tolvaptan on Days 1, 2, 3, and 4, respectively, 
regardless of status as responder/nonresponder.

An early termination (ET) sample will be taken for any subject who is receiving 
tolvaptan.
On Day 2a no PK samples are taken.
For each PK blood sample collected volumes are not expected to exceed 1.2 mL.  Total 
volume per sample may be lower depending on finalization of blood collection supplies.  


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Serum sodium assessments and other clinically necessary blood samples take priority; 
therefore, due to restrictions in allowable total daily blood volumes based on local 
guidelines and subject age, it may not be possible to take more than one PK sample per 
day.  If so, the PK sampling should be changed to:

Day 1: 2 hours postdose (5 minutes)

Day 2: 8 (2) hours postdose (may be concurrent with serum sodium or other 
blood sampling)

Day 3 at trough, ie, predose/24 hours post prior dose (concurrent with serum 
sodium sample)

Day 4 at trough, ie, predose/24 hours post prior dose (concurrent with serum 
sodium sample)
The PK profiles will be evaluated on an ongoing basis to determine the variability
between subjects.  Based on the findings, PK sampling will continue for as long as
necessary to establish suitable estimates of clearance with a 90% CI similar to that
observed in the adult populations.  Once these estimates are achieved, sampling will be
discontinued in subsequent subjects.
For each subject all samples will be collected according to local guidelines and best
practices for pediatric care. If a sample is missing due to limitations in allowable blood 
volumes based on local regulations or local practice this will not count as a protocol 
deviation.
3.7.3.1.2
Sample Handling and Processing
All blood samples will be shipped to the testing facility for analysis.  Detailed handling 
and shipping instructions are provided in Appendix 3.
3.7.3.2
Pharmacodynamic Assessments
3.7.3.2.1
Fluid Intake
Fluid intake (both oral and IV) will be measured at the times presented in the schedule of 
assessments (Section 3.7.1).  The fluid content of foods with significant water content 
(eg, soup) should be added to the total fluid intake.  Fluid intake will be monitored per 
institutional guidelines.
3.7.3.2.2
Urine Volume
Urine volume will be determined in urine samples that will be collected at the intervals 
presented in the schedule of assessments, Section 3.7.1.  All urine voids within a 
collection interval should be kept refrigerated and pooled according to the size of 


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available collection containers.  At the end of the collection interval all samples should be 
pooled and the urine volume determined.  
3.7.3.2.3
Urine Chemistry
Urine chemistry will be determined from pooled urine samples collected for the intervals 
presented in the schedule of assessments, Section 3.7.1.  An aliquot will be taken for each 
collection interval according to the procedures of the local clinical chemistry laboratory.  
The list of urine chemistry tests to be conducted is presented in Table 3.7.4.2.3-1.
3.7.3.2.4
Palatability and Acceptability Assessment
A questionnaire will be administered immediately after dosing to assess palatability to 
rate flavor/taste, smell, sweetness, and overall liking of the study medication.  Subjects 
will also be asked about the ease of swallowing the study medication.  Between 15 to 
20 minutes after dosing, a questionnaire will be administered to subjects again to assess 
overall liking of the study medication.  This assessment will only be done in subjects 
aged 3 years to 18 years.
3.7.4
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.
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 3.7.1 and Section 3.7.4.2.1.
3.7.4.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
In addition, active monitoring is required for:


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
Absolute serum sodium level 145 mEq/L (mmol/L) or an overly rapid rise in 
serum sodium level (an increase in serum sodium of > 8 mEq/L [mmol/L] over a 
10-hour period, 12 mEq/L [mmol/L] over a 24-hour period, or a rate of increase 
in serum sodium concentration that the investigator deems too rapid), 
neurological symptoms, or other signs or symptoms suggestive of osmotic 
demyelination (see Section 0 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 total bilirubin level should also 
be evaluated.  See Section 3.7.4 for more information and Section 5.4.1 for
detailed instructions on how this type of event should be captured.

Worsening symptoms of hyponatremia

Hypovolemia or hypotension requiring intervention
3.7.4.2
Clinical Laboratory Assessments
3.7.4.2.1
Serum Sodium
In addition to serum sodium samples obtained for trial 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 (-1 to + 0.25) hours postdose and at 18 (± 1) hours postdose.  This sodium safety 
assessment will be repeated at 6 (-1 to + 0.25) and 18 (± 1) hours postdose each day for 
the remainder of Treatment Phase A.  A point of care assessment unit is preferred since it 
is expected to reduce overall daily blood volume needed for assessments (expected 
0.5 mL for regular blood draws versus up to several drops for a point of care assessment, 
depending on the device used); however, regular blood draws may be used (especially if 
they can be combined with standard of care labs).
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 unscheduled serum sodium concentrations collected 
as part of standard of care will be reported as unscheduled sodium assessments in the 
electronic case report form (eCRF) through the follow-up sodium assessments.
3.7.4.2.2
Serum Osmolality
Serum osmolality will be calculated to help guide dosing.  Local site personnel will 
determine serum osmolality using one of the following equations:
a) Where Na, glucose, and blood urea nitrogen (BUN) are measured in mg/dL:
Serum Osmolality (mOsm/kg) = 2 Na + BUN / 2.8 + (glucose / 18)


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b) Where Na, glucose, and urea are measured in mmol/L:
Serum Osmolality (mOsm/kg) = 2 Na + glucose + urea
3.7.4.2.3
Clinical Lab Tests
Table 3.7.4.2.3-1 presents required clinical laboratory assessments (serum chemistry, 
hematology, coagulation, urinalysis, and urine chemistry). All clinical laboratory tests 
will be performed by local laboratories.  Serum cortisol and TSH will be measured during
screening using the remaining blood sample obtained for serum chemistry.  If these 
results are obtained as part of the standard of care for the subject, a trial-specific sample 
should be obtained and sent to the local laboratory for analysis per the schedule of 
assessments (Section 3.7.1).  Urine urea will be measured during screening for 
calculation of FE urea.
It is recognized that there may be limitations based on age and weight of children for the 
amount of blood that can be drawn at a single time point, per day, and the overall conduct 
of the trial.  Wherever possible, it is encouraged to combine standard of care samples that 
would be taken regardless of trial participation with those samples required for the trial.
In case of limited blood or urine volume availability, the bolded assessments in Table 
3.7.4.2.3-1 take priority.  Serum sodium and liver function tests are essential to the 
conduct of the trial.


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Table 3.7.4.2.3-1
Clinical Laboratory Tests to be Performed Locally
Hematology:
WBC count with differential
RBC count
Hematocrit
Hemoglobin
Mean corpuscular volume
Mean corpuscular hemoglobin concentration
Platelet count
RBC volume distribution width
Additional Tests:
TSH
Serum cortisol
Coagulation:
International normalized ratio
Platelets
Prothrombin time
Activated partial thromboplastin time
Serum Chemistry:
ALT
Alkaline phosphatase
AST
Bicarbonate (or carbon dioxide)
Bilirubin, total
Urea  or Blood urea nitrogen (BUN)
Calcium
Chloride
Cholesterol, total
Creatinine
Gamma glutamyl transferase
Glucose
Lactic dehydrogenase
Potassium
Protein, total
Triglycerides
Uric acid
Efficacy:
Serum sodium
Urinalysis:
Color
Appearance
Bilirubin
Glucose
Ketones
Leukocytes
Nitrites
Occult blood
Protein
Urobilinogen
Microscopic analysis of RBC/WBC (per high
  powered field)
Urine Chemistry:
Osmolality
Sodium
Potassium
Creatinine
Urea
Additional Test:
Serum or urine pregnancy test (if applicable)
Drug Screen (all items in urine):
Alcohol 
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Methadone
Opiates
Phencyclidine
Additional Drug Screen Test:
Alcohol (breath)
WBC = white blood cell; RBC = red blood cell.
In case of limited blood or urine volume availability the bolded assessments take priority.  Serum Sodium 
and liver function tests are essential to the conduct of the trial.
3.7.4.2.4
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 


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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 total bilirubin level should also 
be evaluated.  These elevated values should be confirmed by retesting.  If 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 
eCRFs.  See Section 5.4.1 for detailed instructions on how this type of event should be 
captured.
3.7.4.3
Physical Examination 
Full and directed physical examinations will be performed and documented according to 
the schedule of assessments (Section 3.7.1).  The initial physical examination should be a 
full physical.  Subsequent physical examinations can be directed physical examinations 
that are focused on hyponatremia-related signs and symptoms as well as any major 
changes from baseline.
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 for a given subject.  Any 
condition present at the post-treatment directed physical examination that was not present 
at Screening 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.  
Neurological examinations will be performed in an age-appropriate manner per 
Section 3.7.4.3.1.
Body weight will be measured predose each day throughout Treatment Phase A, 
Treatment Phase B and at each clinic visit in Follow-up Phase C, as possible.  Every 
effort should be made to ensure that body weight measurements are 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.


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3.7.4.3.1
Neurological Examination
A neurological examination will be performed as part of the directed physical exam per
the schedule of assessments (Section 3.7.1).  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.
3.7.4.4
Tanner Staging
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 where licensing 
permits).  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 investigator will arrive at a single score summarizing the domains (not 
individual domain scores) when evaluating the subject.
3.7.4.5
Vital Sign Assessments
Vital signs (including supine blood pressure, heart rate, respiratory rate, and temperature) 
will be assessed at time points according to Section 3.7.1 of this protocol.  Supine vital 
signs will be taken when the subject has been lying down (bed positioned < 45 degree 
angle) for 3 minutes.  All assessments for vital signs should be performed around the 
time of the formal hyponatremia assessment (sodium blood draw) during Screening, 
Treatment Phase A and Treatment Phase B and anytime during the Follow-up Period
consistent with the timing of other trial assessments.  All vital sign assessments should be 
performed predose and prior to the blood draw at the nominal time point.
3.7.4.6
Electrocardiogram Assessments
One ECG will be recorded at screening, prior to any blood draws.  Twelve-lead ECGs 
will be recorded with the subject supine and at rest (for at least 10 minutes).  Heart rate, 
PR interval, QRS duration, and QT interval will be recorded.  The principal investigator 
or designee will review, sign, and date each ECG reading.  Any abnormalities should be 
reported as part of the medical history.  Whenever possible, the same reviewer should 


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evaluate, sign, and date the ECGs.  A paper copy of the ECG will be sent for storage to a 
central ECG storage facility.
3.7.4.7
Hyponatremia History
Each subject’s hyponatremia medical history will be recorded at screening.  The 
hyponatremia history should include the etiology of subject’s hyponatremia (including 
assessments per Section 3.2.4.2) and what treatment was administered prior to trial 
enrollment.  Symptoms potentially attributable to hyponatremia should be specifically 
assessed for prior history.  The hyponatremia assessment at Screening will consist of 
documentation of hyponatremia etiology (eg, HF, hepatocellular disease [including 
cirrhosis], SIADH/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.
3.7.4.8
Volume Status Assessment
Volume status will be assessed every 6 hours prior to trial entry and every 6 hours during 
Treatment Phase A.
3.7.4.9
Vital Status
An assessment of vital status will be conducted on subjects who terminate prior to the last 
study visit, and do not withdraw consent for continued telephone contact.  The telephone 
contact will be made 14 days post-last dose, and will be conducted with a reliable 
informant; either the subject and/or the parent/guardian, per investigator discretion.  Vital 
status collected and recorded will be:

Subject alive

Subject deceased (date of death, cause of death)
3.7.5
End of Trial
The End of Trial Date is defined as the last Date of Contact or the Date of Final Contact 
Attempt from the Post-treatment Follow-up eCRF page for the last subject completing or 
withdrawing from the trial.
3.7.6
Independent Data Monitoring Committee
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 medical practice.  It may make recommendations 


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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 Arm(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
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/IEC at the site.
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 treatment 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 following the 
first dose of tolvaptan must be withdrawn from the trial:
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 from the trial;
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 (eg, blood draw requirements); see Section 3.12, Subject 
Compliance);
d) At the request of the subject, investigator, OPDC or designee, or regulatory 
authority;
e) Subject becomes pregnant; or
f)
Subject is lost to follow-up.


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Subjects who have clinically relevant TSH or cortisol levels may not respond properly to 
tolvaptan and will be withdrawn from the trial.
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):

Subject’s serum sodium level increases by > 8 mEq/L [mmol/L] in any 10-hour 
period following dosing on Day 1

Subject’s serum sodium level 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]
Subjects who require IV infusion of isotonic or hypertonic saline for hyponatremia or 
who receive another approved/off-label therapy (rescue therapy) for hyponatremia before 
completion of the trial will be withdrawn from trial treatment; these subjects should 
continue to Phase C to be followed.  Subjects, who are randomized to the Early 
Withdrawal group, whose serum sodium level declines by 4 mEq/L (mmol/L), or 
whose overall clinical condition requires further treatment to increase serum sodium level 
will be treated per the investigator’s preferred standard of care.  Any intervention 
intended to raise serum sodium during the first 48 hours of the Early Withdrawal phase 
(including fluid restriction) will be defined as rescue therapy.  The subject will be 
considered to have reached their clinical endpoint, and their data will be censored from 
that time forward.
The sponsor and the medical monitor should be notified promptly when a subject requires
treatment other than trial treatment for the purpose of raising serum sodium.  Subjects 
receiving rescue therapy are to continue to be monitored per protocol (to discharge or 
death).  Subjects terminated prior to completion will not be re-enrolled.
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 14 days after the last study visit for vital status 
(Section 3.7.4.9). 


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3.9
Screen Failures
A screen failure subject is one from whom informed consent/assent (if applicable) has 
been obtained and is documented in writing (ie, the subject’s parent/legal guardian or 
legally acceptable representative signs an ICF), but who is not enrolled into the trial. If a 
subject’s serum sodium level during the Screening period is 130 mEq/L [mmol/L], that
subject will be determined a screen failure. Subjects who are deemed screen failures may 
be rescreened for possible participation if they have not taken a dose of IMP.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the tolvaptan.  
For purposes of this trial, subjects who are randomized responders and who complete 
required trial assessments (including their assigned trial treatment) through the end of the 
trial will be defined as responder trial completers.
For purposes of this trial, subjects who are nonresponders (not randomized) but who 
complete required trial assessments through the end of the trial will be defined as
nonresponder trial completers.
Subjects who discontinue tolvaptan prior to the end of Treatment Phase B, but who 
continue in the trial and complete some or all of their required assessments to the end of 
the trial, will be considered “early” end of treatment (EEOT) completers.  
3.11
Definition of Lost to Follow-up
Subjects or subjects’ parent(s)/legal guardian(s) or legally acceptable representative(s)
who cannot be contacted on or before the final Follow-up Contact at 14 days post-last 
dose 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).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 


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the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.12
Subject Compliance
All subjects in this trial who deviate from assigned treatment will be considered 
noncompliant.
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 due to an emergency, accident, or 
mistake (eg, violation of informed consent/assent process, IMP dispensing or subject 
dosing error, 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 INC Research 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 INC Research, and reviewed by the site monitor.
4
Restrictions
4.1
Prohibited Medications
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.  Tolvaptan is a sensitive CYP3A4 substrate; plasma concentrations 
increased approximately 4-fold when tolvaptan was administered with the potent 
CYP3A4 inhibitor ketoconazole.14,23  Where appropriate dose reductions are possible, 
tolvaptan doses may be coadministered with potent or moderate CYP3A4 inhibitors (see 
Section 2.1.1 and Table 3.2.3-1).
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 until 24 hours post-last 
dose of IMP.  In addition, the use of alcohol within 72 hours prior to dosing and during 
the trial is prohibited.
Other treatment for the purpose of increasing serum sodium, eg with urea, lithium, 
demeclocycline, conivaptan or tolvaptan, concurrent with dosing of trial medication or 
within 4 days of qualifying serum sodium assessments at screening is prohibited.
The use of saline in this population should be closely monitored.  The use of hypertonic 
saline (3% or greater), including normal saline challenge within 8 hours of the qualifying 
screening serum sodium laboratory assessment 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.  
The use of normal saline (0.9%) is allowed during screening until the beginning of 
Treatment Phase A; normal saline use can resume in Phase C.  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.


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5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as medical 
history at screening for pre planned procedures for which the underlying condition was 
known and no worsening occurred.  An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.  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.
An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions.

Requires in-patient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious adverse events are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event (IRE):


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
Any SAE.

Any AE related to occupational exposure.

Potential Drug Induced Liver Injury (DILI) case (see Section 5.4). 

Pregnancies are also defined as IREs.  Although normal pregnancy is not an AE, 
it will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor.  Pregnancy will only be documented on the AE eCRF if there is an 
abnormality or complication.
Clinical Laboratory Test Value Changes:  It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available.  This review will be 
documented by the investigator’s dated signature on the laboratory report.  For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject.  This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed.  The investigator may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests.  If this laboratory value is 
considered medically relevant by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF.  The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related: 
There is no temporal or causal relationship between the IMP and 
the AE.
5.2
Eliciting and Reporting Adverse Events
The investigator 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 


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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 the 
sponsor.  Serious AE collection is to begin after a subject has signed the ICF.
Use medical terminology in AE reporting.  Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms.  Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3.  Special attention should 
be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, DILI, or confirmed pregnancy, by telephone, fax, or e-mail to 
INC Research as outlined in Appendix 1.  An IRE form must be completed and sent by 
e-mail, 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 over rapid correction does not occur in this 
pediatric population.


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Rapid correction of hyponatremia is defined as any increase in serum sodium 
.  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.
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 total bilirubin level should also be 
evaluated.  Elevated values should be confirmed via retest.  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 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 total bilirubin 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 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 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) 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 drug-induced liver injury 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 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%) 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.  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.31,32
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 
oopherectomy 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 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, condom with 
spermicide, or sponge with spermicide.  The following 3 contraceptive methods are not
allowed in this trial:  birth control pills, birth control depot injection, and birth control 
implant.  Any single method of birth control, including vasectomy and tubal ligation, may 


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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/legal /guardian or legally acceptable 
representative must sign an ICF stating that the above-mentioned risk factors and the 
consequences were discussed with the subject and/or the parent/legal guardian or legally 
acceptable representative.
A urine and/or serum pregnancy test for human chorionic gonadotropin (hCG) will be 
performed at screening on all WOCBP and 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 INC Research [see Appendix 1 for contact information].)


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The investigator must immediately notify 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 this trial, information on AEs will be followed for up to 14 days post-last dose for all 
subjects or until resolution, whichever is longer.
5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status noted.  If a subject has an AE or has not recovered from 
an AE at the last scheduled contact, follow-up contacts will be scheduled at least every 
4 weeks until resolution of the AE is confirmed or the condition is considered clinically 
stable.  All nonserious 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 post-last 
dose or until resolution of the SAE, whichever is longer.
Serious AEs that are identified or ongoing at 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 reported
SAEs, or new SAEs.  The investigator will follow SAEs until the events are resolved, 


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stabilized, or the subject is lost to follow-up.  Resolution means that the subject has 
returned to the baseline state of health and stabilized means that the investigator does not 
expect any further improvement or worsening of the subject’s condition.  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 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.
6
Pharmacokinetic/Pharmacodynamic Analyses
6.1
Pharmacokinetic Analysis
Tolvaptan and metabolite plasma concentrations will be summarized using descriptive 
statistics (n, median, mean, standard deviation [SD], percent coefficient of variation 
[CV], minimum, and maximum) by dose group and time point.  Plasma PK parameters, 
including tolvaptan Cmax, tmax, AUC0-24h, and clearance (dose divided by AUC0-24h) on 
Day 1, and volume of distribution on Day 1, will be summarized using descriptive 
statistics by dose group and age group (age 
 
.  These parameters 
will be analyzed to assess the potential effects of age, sex, race, and disease state on 
tolvaptan PK.
A population analysis will be performed and reported separately.
6.2
Pharmacodynamic Analysis
Urine volume will be summarized by 6-hour intervals using descriptive statistics.  Fluid 
intake and the calculated value of fluid balance will be summarized for each 6-hour 
period and for the 24-hour daily interval on Days 1 and 2 in Treatment Phase A using 
descriptive statistics.  A subgroup analysis by the disease etiology of hyponatremia or by 


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fluid status (euvolemic, hypervolemic) may be conducted if there are sufficient subjects 
in each category.
Urine osmolality and urine creatinine, potassium, and sodium concentrations will be 
summarized by collection interval and for zero to 24 hours on Days 1 and 2 in Treatment 
Phase A using descriptive statistics.
Missing urine concentrations or volumes will not be imputed.  All calculations will use 
nominal times.
If urine volume during a collection interval is zero, then the amount excreted for that 
interval will be set to missing; values for 24 hours will be determined.
Correlations between urine output or fluid balance and change in serum sodium 
concentration may be explored graphically.
Correlations between tolvaptan AUC values and urine output on Day 1 may be explored 
graphically.
7
Statistical Analysis
7.1
Sample Size
7.1.1
Sample Size for Efficacy
A total of 70 randomized subjects will provide 90% power to detect a treatment 
difference of 4 mEq/L (mmol/L) in change in serum sodium from Day 2 (or 2a) at the 
end of Treatment Phase A to the end of Treatment Phase B using a 2-sided alpha of 0.05.  
An SD of 5 in change of serum sodium was used for the sample size calculation.  After 
the end of Treatment Phase A at Day 2 (or 2a), subjects will be randomized at a ratio of 
1:1 to either continue treatment with tolvaptan for 2 additional days (Late Withdrawal) or 
to discontinue tolvaptan treatment (Early Withdrawal).  Sample size re-estimation will be 
conducted when 90% of the subjects finish (complete or discontinue) the trial.  The trial 
must include no fewer than 60 subjects on IMP for the assessment of safety based on 
regulatory feedback.
7.1.2
Sample Size for Pharmacokinetic Parameters
Sample size to establish similarity between the CIs for PK parameter estimates between 
adults and pediatrics is based on PK data of clearance.  
 
 
.  To be conservative, it is assumed that the CV of clearance is 0.42.  In 


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order to establish a 95% CI within 60% and 140% of the point estimate for the geometric 
mean estimate of clearance in an age group (age < 10 or 10 years), under the 
assumption that the geometric means estimates of clearance are equal between adult and 
pediatric subjects, CIs of the ratio of geometric means of pediatrics and adults will be 
constructed.  Twenty pediatric subjects and 80 adult subjects are needed to have 90% 
power to establish a 95% CI of the ratio of geometric means within 0.71 and 1.40.  In the 
actual analysis, all 81 adult subjects’ data will be used.
7.2
Datasets for Analysis
The following samples are defined for this trial:

Enrolled Sample consists of all subjects for whom an ICF/assent form was signed 
for the trial.

Treatment Phase A Safety Sample consists of all subjects who receive at least one 
dose of IMP in Treatment Phase A of the trial.

Treatment Phase B Safety Sample consists of all randomized late withdrawal 
subjects who receive at least one dose of IMP in Treatment Phase B of the trial
and all randomized early withdrawal subjects.

Treatment Phase A Efficacy Sample consists of all subjects who are in Treatment 
Phase A Safety Sample and have baseline and at least one post-baseline efficacy 
evaluation in Treatment Phase A.

Treatment Phase B Efficacy Sample is based on the intent-to-treat (ITT) principle; 
the full analysis dataset will be composed of all subjects who are in the Treatment 
Phase B Safety Sample and have both baseline and at least one post-baseline 
efficacy evaluation in Treatment Phase B.
Core dataset for efficacy analyses will be based on the ITT population.  In order to handle
missing data and restrictions imposed by different types of analyses (eg, change from 
baseline analysis), datasets derived from the ITT dataset will be used for the efficacy 
analyses.
7.3
Handling of Missing Data
For the primary endpoint analysis, missing data will be handled by analysis of 
mixed-model repeated measures (MMRM) methodology under the assumption of missing 
at random.  The MMRM analysis will be performed based on the observed cases (OC) 
data.  In order to assess sensitivity of results due to missing data, last observation carried 
forward (LOCF) analysis will be performed as a sensitivity analysis.  In contrast to the 
OC dataset, which will consist of the actual observations recorded at each visit, the LOCF 
dataset will include data recorded at a scheduled visit (ie, all OC data, or, if no 
observation is recorded at that visit, data carried forward from the previously scheduled 


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visit).  Baseline data will not be carried forward to impute missing values for the LOCF 
dataset.
7.4
Primary and Secondary Outcome Analysis
7.4.1
Primary Outcome Analysis
The primary endpoint in this trial is the change in serum sodium level for responders 
from Day 2 (or 2a) at the end of Treatment Phase A (where all subjects receive tolvaptan) 
to the end of Treatment Phase B for the Early compared to Late Withdrawal groups.  The 
null hypothesis of this comparison is that there is no difference between the Late and the 
Early Withdrawal groups in change of serum sodium level from Day 2 (or 2a) at the end 
of Treatment Phase A to the end of Treatment Phase B.  The analysis of the primary 
endpoint is based on the Treatment Phase B Efficacy Sample.  Once a subject is 
randomized to Treatment Phase B, any additional therapies for the purpose of raising 
serum sodium, including fluid restriction, will be considered rescue therapy.  Upon 
receipt of rescue therapy, a subject’s endpoint data will be collected and then censored 
thereafter.  The primary analysis of this protocol is based on the data collected in this 
manner.
A sensitivity analysis will be provided to include serum sodium data collected while an 
Early Withdrawal subject is under fluid restriction for the analysis of the primary 
endpoint.  This sensitivity analysis would become the primary analysis if at least 30% of 
the Early Withdrawal subjects do not have serum sodium data at 24 and 48 hours 
post-randomization due to application of fluid restriction in the withdrawal phase of the 
protocol.
The MMRM analysis with an unstructured variance covariance structure based on the OC 
dataset will be performed on the primary endpoint.  The MMRM model will include 
fixed effect of treatment, age subgroup 
, serum 
sodium response subgroup (
), underlying etiology (
 
, visit, treatment visit 
interaction, and covariate of baseline and baseline visit interaction.  Statistical test of the 
least squares (LS) mean differences between treatment groups at the end of Treatment 
Phase B of the MMRM analysis will serve as the primary analysis.
As a sensitivity analysis, analysis of covariance with baseline value as covariate and 
treatment, age subgroup, serum sodium response subgroup, and underlying etiology of 
hyponatremia as factors will be applied to the LOCF dataset.  Treatment comparison 
between the Late and Early Withdrawal groups will be conducted by comparing LS 
means.


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For the primary endpoint analysis, baseline is the last evaluation of serum sodium level in 
Treatment Phase A prior to randomization.
7.4.2
Secondary Outcome Analyses
7.4.2.1
Secondary Efficacy Outcome Analyses
For all subjects, the key secondary endpoint is the change in serum sodium concentration 
at the end of Day 2 (or 2a) at the end of Treatment Phase A.  The analysis of the key 
secondary endpoint will be based on the Treatment Phase A Efficacy Sample.
A paired Student’s t-test will be used to analyze the key secondary endpoint.
For the key secondary efficacy analysis, a hierarchical testing procedure will be used to 
maintain the overall experiment-wise type I error rate at 0.05.  Thus, if the primary 
efficacy analysis yields a statistically significant result at alpha level of 0.05 (2-sided), 
then the paired t-test will be performed at an alpha level of 0.05 for the key secondary 
endpoint.
Baseline for the key secondary analysis is the last evaluation prior to first dose of IMP in 
Treatment Phase A.
7.4.2.2
Secondary Safety Outcome Analyses
Other secondary endpoints include:

Percentage of subjects with overly rapid increase in serum sodium level
.

Change in serum sodium level from 24 hours post-last dose to 7 days post-last 
dose.

Percentage of subjects requiring rescue therapy (other than fluid restriction)
during Treatment Phase A and Treatment Phase B.

Percentage of subjects requiring fluid restriction during Treatment Phase A and 
Treatment Phase B.

Other secondary safety outcomes to be assessed are presented in Section 3.5.3.1
(Vital signs, blood pressure, clinical laboratory tests, body weight, and 
neurological examinations)
Descriptive statistics along with 2-sided 95% CIs will be applied for percentage of 
subjects with overly rapid increase in serum sodium and percentage of subjects requiring 
rescue therapy or fluid restriction.
The change in serum sodium level from 24 hours post-last dose to 7 days post-last dose
will be summarized using a paired Student’s t-test.


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7.4.2.3
Pharmacokinetic Parameters
Previously obtained PK data from 81 adult subjects who received a 30-mg dose of 
tolvaptan will be included in the analysis to show the similarity for PK parameter 
estimates between adult and pediatric subjects.  An analysis of variance model will be 
performed on the natural-log transformed PK parameters using the MIXED procedure in 
SAS, in which only one fixed effect of subject group (pediatric and adult groups) is 
included in the model.  The anti-logs of the difference of LS means and the confidence 
limits will provide the estimate and 90% CI for the ratio of the geometric means of 
pediatric group and adult group.  Similarity of a PK parameter between pediatrics and 
adults will be indicated if the 90% CI for the ratio of the population geometric means is 
contained within the equivalence limits of 0.6 to 1.4.
7.4.3
Exploratory Outcome Analyses
Details will be provided in the statistical analysis plan.
The change in serum sodium concentration in nonresponders continuing on tolvaptan 
therapy by change from baseline at the end of Treatment Phase B compared to the end of 
Treatment Phase A will be analyzed using a paired Student’s t-test.  
The procedure for the analysis of data for the QoL assessments will be provided in the 
statistical analysis plan (SAP).
The analysis for the following exploratory PD endpoints is described in Section 6.2:

In all subjects, 24-hour excretion of sodium, creatinine, and osmolality on Days 1 
and 2

24-hour sodium clearance on Day 1
7.4.4
Interim Analysis
It was recommended by the FDA that the sample size should be re-estimated when 
approximately 90% of the subjects had finished the trial.  The sample size re-estimation 
will assess the variability of change from Day 2 (or 2a) at the end Treatment Phase A to 
the end of Treatment Phase B in serum sodium level by using the pooled variance of the 
2 treatment groups.  At the trial planning stage, an SD of 5 was used to detect a treatment 
difference of 4, resulting in a sample size of 70 with a 2-sided alpha of 0.05 and 90% 
power.  In case the variance ratio (equal to the observed pooled variance divided by 25, 
the square of 5 as an SD used in the sample size calculation) is 1, no sample size 
increase will be made, and the trial will proceed to finish enrollment of 70 randomized 
subjects.  In case the variance ratio is > 1, the sample size re-estimation will be equal to 


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70 multiplied by the variance ratio, then rounded up to the nearest even number.  Table 
7.4.4-1 provides an example of the sample size re-estimation under different variance 
ratios.
Table 7.4.4-1
Sample Size Re-estimation
Variance Ratio
Sample Size
1.1
78
1.2
84
1.3
92
1.4
78
1.5
106
7.5
Analysis of Demographic and Baseline Characteristics
Demographic characteristics and medical history at Screening will be summarized by 
descriptive statistics, eg, proportion, mean, median, SD, minimum, and maximum values.  
These summary statistics will be reviewed to identify any potential lack of balance 
between the groups.
7.6
Safety Analysis
Safety analysis will be conducted based on the Safety Samples, which are defined in 
Section 7.2.  Safety variables (in addition to those listed in Section 7.4.2.2) 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.
Safety analyses will be performed for Treatment Phase A and Treatment Phase B 
separately.
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 by treatment group:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP 


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The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
7.6.2
Clinical Laboratory Assessment 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.
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 
analysis will be performed on physical examination data.  Physical examination data will 
be listed.
8
Management of Investigational Medicinal Product
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 in blister packs or 
as 60 mL bottles containing 1 mg/mL (0.1% w/v) tolvaptan suspension.  Each blister 
pack and suspension bottle used in the dosing period will be labeled to clearly disclose 
the 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.  Each site will be supplied with bottle(s) 
containing placebo tablets to use for subject screening purposes.  Each placebo bottle will 
be labeled to clearly disclose the compound ID, trial number, instruction for use, route of 
administration, appropriate precautionary statement, and other information required by 
the local regulatory authorities.  For dosing suspension, syringes and bottle adaptors will 
be made available to the sites.
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.


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The IMP blister packs will be stored at 25C (77F) or below, with excursions allowed 
from 15 to 30C (59 to 86F).  The IMP suspension bottles will be stored at 2 to 8C 
(35.6 to 46.4F) and protected from light. The clinical site staff or designated personnel 
will maintain a temperature log in the IMP storage area recording the temperature at least 
once each working day.
8.3
Accountability
The investigator, or designee, must maintain an inventory record of IMP received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused and/or partially used IMP must be 
returned to 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.
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


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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 the 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
OAPI-EQCProductComplaints@Otsuka-us.com

Phone – Rocky Mountain Call Center at +1-800-438-6055
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
Information required for reporting purposes include:

Description of complaint

Reporter identification (eg, subject, investigator, site)

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
During the report of the PQC, it should be indicated whether the complaint sample is 
available for return.  If the complaint sample is available for return, the sample should be 
returned in the product retrieval package, which will be provided by Otsuka America 
Pharmaceutical, Inc.-Ethics, Quality and Compliance (OAPI-EQC).
It should 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.


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9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the 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 clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, 
the review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings.  The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed;

The signature (or initials) and date of each clinician (or designee) who made an 
entry in the progress notes.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.  Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by a site 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 


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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 E630 and as required by applicable local regulations.  
The investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.
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 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, 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.


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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.
10.2
Auditing
The sponsor’s Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not be limited to, IMP 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 during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6),
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science 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 eCRFs, 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.


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12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region(s) where the trial 
is conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  All IMPs, subject bodily fluids, and/or other 
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the sponsor.
Subjects will be identified only by unique subject 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 IMP(s) 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 


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continued participation and before the amendment-specified changes in the trial are 
implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
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;25:1225-
38.
5
Adrogue HJ. Consequences of inadequate management of hyponatremia. Am J 
Nephrol. 2005;25:240-9.


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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 Adrogue HJ, 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
, et al. Therapeutic effects of titration dosing of OPC-41061 in a rat 
experimental SIADH model. Otsuka Study No. 019174, Otsuka Report No. 015404, 
2003.
14 Otsuka Pharmaceutical Development & Commercialization, Inc.  OPC-41061 
Investigator’s Brochure, edition 21.  Otsuka Report, issued 25 Aug 2015.
15
. 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 08 Oct 2004.
16 Makinen K. 1984. Effect of long-term, peroral administration of sugar alcohol on 
man. Swed. Dent. J. 8:113-124.
17 National Center for Health Statistics, National Center for Chronic Disease Prevention 
and Health Promotion. Clinical Growth Charts [available on the Internet]. Last 
updated Nov 2000.
18 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].
19 US Department of Health and Human Services:  Guidance for Industry:  E11 Clinical 
Investigation of Medicinal Products in the Pediatric Population.  ICH December 
2000.
20
  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.


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21
. 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.
22
. Physiologically-based pharmacokinetic modeling of tolvaptan for the 
prediction of syrup suspension doses in pediatric subjects from 4 Weeks to 4 years of 
age. Otsuka Clinical Study Report for Protocol 156-13-214, issued 27 Feb 2014, 
amended 13 Mar 2014.
23
 A Randomized Double-Blind Study to Assess the Safety and 
Pharmacokinetics of Concomitant Administration of Orally Administered OPC 41061 
Tablets and Ketoconazole in Healthy Adult Male and Female Volunteers. Otsuka 
Clinical Study Report for Protocol 156-98-201, issued 07 Dec 2000, amended 15 Feb 
2001, 28 May 2003, and 03 Mar 2004.
24 Moritz ML, Ayus JC. Preventing neurological complications from dysnatremias in 
children. Pediatr Nephrol. 2005;20:1687-700.
25 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.
26 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-S21. 
27 Karp BI, Laureno R. Pontine and extrapontine myelinolysis; a neurologic disorder 
following rapid correction of hyponatremia. Medicine. 1993;72:359-73.
28 El-Kabbani O, Darmanin C, Chung RP. Sorbitol dehydrogenase: structure, function 
and ligand design. Curr Med Chem. 2004 Feb;11(4):465-76.
29 Mayatepek E, Hoffmann B, Meissner T. Inborn errors of carbohydrate metabolism. 
Best Practice & Research Clinical Gastroenterology. 2010;24:607-618.
30 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].
31 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].
32 U.S. Food and Drug Administration.  [homepage on the Internet].  Silver Spring:  
[updated 05 Aug 2015; cited 12 Nov 2015].


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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)
:
Phone 
; Fax 
t
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:
Phone 
; Mobile 
Fax:  
E-Mail:
Trial Management & Clinical 
Monitoring
INC Research
3201 Beechleaf Court, Suite 600
Raleigh, North Carolina 27604-1547, USA
Phone:  
Electronic Data Capture
MediData Solutions
79 Fifth Avenue, 8th Floor
New York, New York 10003, USA
Phone:  
Fax:  
Investigational Materials
Fisher Clinical Services
7554 Schantz Road
Allentown, Pennsylvania 18106, USA
Phone:  
Fax:  
Study Communications & Patient/Site
Support
Matthews Media Group 
700 King Farm Boulevard, Suite 500
Rockville, MD 20850, USA
Phone: 
IRT Systems (treatment randomization)
S-CLINICA
1500 Market Street
12th Floor East Tower
Philadelphia, Pennsylvania 19102, USA
Phone:  
Central ECG Storage
eResearch Technology, Inc.
1818 Market Street
Philadelphia, Pennsylvania 19103, 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 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 
eCRF, not the scheduled time for the drawing.  The exact time of dosing should also be 
noted.
Plasma Samples for Tolvaptan
Blood will be collected into 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 in a freezer at -20◦C or colder or on dry ice.  Samples 
should be shipped after a subject has completed treatment and the final PK sample has 
been drawn and processed so as to include the entire set of samples for each subject 
within one shipment.
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.


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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
Protocol Amendments
Amendment Number:
1
Issue Date:
04 Nov 2013
PURPOSE:

To update the clinical management representative for this trial

To remove the serum chemistry assessment at 7 (1) days post-randomization

To change the sample size from 80 to 70 responders

To clarify that subjects who cannot safely swallow the tablet are excluded until a 
liquid formulation is available

To add neurological exam as an exploratory variable

To update the dosing rationale based on starting doses (mg/kg) used for 
hyponatremia trials of tolvaptan in adults

To change early termination from the 7-day Follow-up Visit to Day 5/6

To clarify that Phase B (Randomization Phase) applies to all subjects

To correct the definition of a rapid correction of serum sodium

To update the interim analysis

To update the contact list for reporting an IRE
BACKGROUND:  This protocol is being amended to provide a more developed 
argument for the dosing rationale.  The statistical section has also been updated.
MODIFICATIONS TO PROTOCOL:

Bold and underlined text:
Changed Text

Bold and strike through text:
Deleted Text

Bold and italicized text:
Added Text
COVER PAGE
Added and Changed Text:
REVISED CLINICAL PROTOCOL
Clinical Management
t
Phone 
; Fax


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E-mail:  
Phone 
; Fax 
E-mail:  
Date of Amendment 1:
04 Nov 2013
FOOTER
Changed Text:
Final 03 Jul 2013 Amendment 1:  04 Nov 2013
SYNOPSIS TRIAL DESIGN
Deleted Text:
Phase C (Follow-up Phase):  All subjects will be monitored and treated as clinically 
warranted per the investigator’s preferred standard of care for up to 3 additional days 
after the last dose of tolvaptan (note:  the Early Withdrawal group should be 
monitored for the first 48 hours post-last dose).  All subjects will have an additional 
serum sodium measurement at 72 (4) hours post randomization and 7 (1) days 
post-randomization.  An additional chemistry panel will also be collected 
7 (1) days post-randomization.  A final safety follow-up telephone contact/visit 
will be performed 14 (+ 2) days post-last dose.
SYNOPSIS SUBJECT POPULATION
Changed Text:
This trial will include up to 100 male and female subjects aged 4 weeks (or 
44 weeks adjusted gestational age for premature births) to < 18 years who have 
been diagnosed with euvolemic or hypervolemic hyponatremia (< 130 mmol/L) that 
persists despite initial standard background therapy (including fluid restriction and 
excluding a vasopressin antagonist).  It is expected that 80 70 subjects will have a 
serum sodium increase of 4 mmol/L (ie, responders).
Eighty Seventy randomized subjects will provide 90% power to detect a treatment 
difference of 4 mmol/L in change in serum sodium from randomization (at the end of 
Day 2/3 [Phase A]) to the end of Day 4/5 (2 days after randomization [Phase B]).  
Age groups will be stratified such that half (40 35) of these subjects will be 
< 10 years old with at least 25% (20 17) of subjects < 6 years old.  Subjects who are 


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defined as responders will be further stratified by the magnitude of serum sodium 
response to tolvaptan (7 and > 7 mmol/L) and underlying etiology of hyponatremia.
SYNOPSIS INVESTIGATIONAL MEDICINAL PRODUCT, DOSE, FORMULATION, 
MODE OF ADMINISTRATION
Changed Text:

Subjects < 2 years of age, or weighing < 10 kg, or who cannot safely swallow 
the tablet will be excluded until the availability of a liquid formulation.  Dosing 
information will be available at that time.
SYNOPSIS CRITERIA FOR EVALUATION
Added Text:
Exploratory Endpoints:
Efficacy:

In nonresponders continuing on tolvaptan therapy, change in trough serum 
sodium concentration on Day 6 compared to Day 4
Safety:

Neurological examinations
Pharmacodynamic:

In all subjects, 24-hour excretion of sodium, creatinine, and osmoles on Days 1 
and 2

24-hour sodium clearance
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Added Text:
BW
Body weight
Section 2.1 TRIAL RATIONALE
Changed Text:
The proposed population size of 100 subjects should provide 80 70 responders, which 
has adequate power (> 90%) to test for statistical significance in the primary 
endpoint.  Enrollment is expected to take 3 years using up to 50 sites globally.  
Additional blood sampling will be included across populations to provide PK 
information.


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Section 2.1.1 DOSING RATIONALE
Added and Changed Text:
Enrolled subjects will be dosed 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.17  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 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 2.1.1-1 outlines the mg/kg dose ranges for 
tolvaptan tablet doses and body weights of 10, 20, 50, 70 (standard adult man), 
and 100 kg.
Table 2.1.1-1
Proposed Tolvaptan 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
15 mg
-
-
0.30
0.21
0.15
7.5 mg
-
0.375
0.15
-
-
3.75 mg
0.375
0.19
-
-
-
BW = body weight.
Tolvaptan is a sensitive CYP3A4 substrate; plasma concentrations increased 
approximately 4-fold when tolvaptan was administered with the potent CYP3A4 
inhibitor ketoconazole.13,20  Where appropriate dose reductions are possible, 
tolvaptan doses may be coadministered with potent or moderate CYP3A4 
inhibitors.


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Section 3.1 TYPE/DESIGN OF TRIAL
Deleted Text:
Phase C (Follow-up Phase):  All subjects will be monitored and treated as clinically 
warranted per the investigator’s preferred standard of care for up to 3 additional days 
after the last dose of tolvaptan (note:  the Early Withdrawal group should be 
monitored for the first 48 hours post-last dose).  All subjects will have an additional 
serum sodium measurement at 72 (4) hours post randomization and 7 (1) days 
post randomization.  An additional chemistry panel will also be collected 
7 (1) days post-randomization.  A final safety follow-up telephone contact/visit 
will be performed 14 (+ 2) days post-last dose.
Figure 3.1-1 TRIAL DESIGN SCHEMATIC
Added Text:
aSubjects must be 2 years of age and weigh 10 kg until development of a liquid 
formulation is complete.
Section 3.2 TREATMENTS
Added Text:
Subjects who cannot take an oral tablet are currently excluded due to their inability 
to safely swallow the spray-dried tablet.  Subjects weighing < 10 kg are also 
excluded as that weight has not been studied in previous PK trials and, therefore, 
the dose of tolvaptan being delivered is not confirmed.  To support the enrollment 
of these subjects, an age and weight appropriate suspension formulation is being 
developed.  Once available, the protocol will be amended to include the 
formulation.
Consequently, the maximum starting dose for subjects weighing > 50 kg is slightly 
less than 0.30 mg/kg; starting doses for subjects weighing 20 to 50 kg, inclusive, 
range from 0.38 to 0.15 mg/kg; starting doses for subjects weighing 10 to < 20 kg 
range from 0.375 mg/kg to slightly greater than 0.19 mg/kg.  Therefore, the 
maximum starting doses planned for this pediatric trial are in the range previously 
used in adult hyponatremic subjects.
Deleted Text:
Some very young subjects will not be able to safely swallow the spray-dried 
tablet.  To support the enrollment of these subjects, an age appropriate 
suspension formulation is being developed.  Once available, the protocol will be 
amended to include the formulation.


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Section 3.3 TRIAL POPULATION
Changed Text:
This trial will include up to 100 male and female subjects aged 4 weeks (or 
44 weeks adjusted gestational age for premature births) to < 18 years, who have 
been diagnosed with euvolemic or hypervolemic hyponatremia (< 130 mmol/L) that 
persists despite initial standard background therapy (including fluid restriction and 
excluding a vasopressin antagonist).  It is expected that 80 70 subjects will have a 
serum sodium increase of 4 mmol/L (ie, responders).
Age groups will be stratified such that half (40 35) of these subjects will be age 
< 10 years with at least 25% (20 17) of subjects < 6 years old.  Subjects who are 
defined as responders will be further stratified by the magnitude of serum sodium 
response to tolvaptan (7 and > 7 mmol/L) and underlying etiology of hyponatremia.
Section 3.5.3.2 SAFETY VARIABLE
Added Text:
3.5.3.2 Safety Variable
The other safety variable is neurological examinations.
Section 3.7 TRIAL PROCEDURES
Deleted Text:
Treatment in this trial will be up to 5 days.  Any initiation or titration of tolvaptan 
must occur in a hospital setting.  Parents or legal guardians will consent and subjects 
will assent (as appropriate) and be screened up to 24 hours prior to dosing.  Subjects 
who meet the inclusion and exclusion criteria will be enrolled and will be 
administered a 3.75-, 7.5-, or 15-mg dose based on age, weight, and the use of 
CYP3A4 inhibitors.  At the end of Treatment Day 2 (optionally Day 3 [Phase A]), 
subjects who are responders will be randomized to either continue treatment with 
tolvaptan for 2 additional days (Late Withdrawal) or to discontinue tolvaptan 
treatment (Early Withdrawal).  Subjects who are nonresponders may continue on 
tolvaptan therapy for 2 additional days at their highest dose or may be withdrawn 
from tolvaptan to be treated per the investigator’s preferred standard of care.  During 
Phase B, subjects in the Late Withdrawal group and nonresponders continuing 
treatment will continue treatment with tolvaptan for 2 additional days and all subjects 
will have serum sodium measured every 12 (4) hours post-randomization.  In 
Phase C, or Follow-up Phase, subjects will be monitored and treated as clinically 
warranted per the investigator’s preferred standard of care for up to 3 additional days 
after the last dose of tolvaptan (note:  the Early Withdrawal group should be 
monitored for the first 48 hours post-last dose) and will have an additional serum 


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sodium concentration measurement at 72 (4) hours post randomization and 
7 (1) days post-randomization.  An additional chemistry panel will also be 
collected at 7 (1) days post-randomization.  A final safety follow-up telephone 
contact/visit will be performed 14 (+ 2) days post-last dose.


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Table 3.7-1 SCHEDULE OF ASSESSMENTS
Changed Text:
Table3.7-1
Schedule of Assessments
Procedures
Phase A
Phase B
Phase C
Screening/
Baseline Visit 
Days −2 to −1
Initial Treatment Phase
Days 1 and 2/3
Randomization 
Phase
Days 3/4 and 4/5
Follow-up 
Phase
Day 5/6 or ET
Follow-up 
(7 [1] days 
post-random.)
or ET
Follow-up 
Phone Call/Visit 
(14 [+ 2] days 
post-random.)
Informed consent and assent
X
Review inclusion/exclusion
  criteria
X
Day 1:  predose
Demographic information
X
Medical and hyponatremia
  history
X
Alcohol and drug screen
X
Pregnancy test (if applicable)a
X
Serum chemistry
X
X
X
Serum osmolality, FeNa, and 
  Fe urate
X
TSH and cortisolb
X
Hematology and coagulation
X
X
Urinalysis
X
X
Urine chemistry
X
Days 1 and 2 only:  6-hour 
intervals starting at Hour 0
Serum sodiumc
2 assessments at 
least 12 hours 
apart
Baseline (Hour 0; within 
3 1 hours of dosing), 
12 hours post-first dose, and 
24 (4) hours post-previous 
dose
12, 24, 36, and 
48 (4) hours 
post-random.
72 (4) hours 
post-random.
X


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Table3.7-1
Schedule of Assessments
Procedures
Phase A
Phase B
Phase C
Screening/
Baseline Visit 
Days −2 to −1
Initial Treatment Phase
Days 1 and 2/3
Randomization 
Phase
Days 3/4 and 4/5
Follow-up 
Phase
Day 5/6 or ET
Follow-up 
(7 [1] days 
post-random.)
or ET
Follow-up 
Phone Call/Visit 
(14 [+ 2] days 
post-random.)
Vital signsd
X
2, 4, 8, and 24 hours 
post-first dose and on Day 3, 
if applicable
X
X
X
Fluid intake and urine volume
Days 1 and 2 only:  6-hour 
intervals starting at Hour 0
PK plasma samplese
1, 2, 4, 12, and 24 hours 
post-first dose
24 and 48 hours 
post-random.
ET only
ET only
12-lead ECG
X
Directed physical examination
X
Baseline (Hour 0), 8 hours 
post-first dose, and Day 2/3
Daily
X
X
Neurological examination
X
Baseline (Hour 0), 8 hours 
post-first dose, and Day 2/3
Daily
X
X
Body height and weightf
X
Daily (predose):  weight only
Daily (predose):  
weight only
Weight only
Weight only
Clinical assessmentg
X
End of Day 2/3
Day 4/5
X
X
Randomization
Responders:  End of Day 2 
(optionally Day 3)
Tolvaptan dosingh
Once daily
Once dailyi
Follow-up phone call
X
Concomitant medications
<------------------------------------------------------------------------------------------------------------------------------------------------>
Adverse events
<------------------------------------------------------------------------------------------------------------------------------------------------>


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Section 3.7.1.1 PHASE B:  RANDOMIZATION PHASE
Added Text:
The following procedures will be performed on Days 3/4 and 4/5 for all subjects:
Section 3.7.1.3.1 FOLLOW-UP (DAY 5/6)/EARLY TERMINATION
Added Text:
3.7.1.3.1 Follow-up (Day 5/6)/Early Termination
The following procedures will be performed on Day 5/6 or at early termination (ET)
for all subjects:
4) A blood sample for PK analysis of tolvaptan will be collected at ET only if ET 
occurs before the last scheduled PK assessment (ie, 48 hours post-randomization 
for subjects continuing on tolvaptan).
Section 3.7.1.3.2 FOLLOW-UP
Deleted Text:
3.7.1.3.2
Follow-up/Early Termination
Subjects will be assessed for maintenance of normal or target serum sodium 
concentration at 7 (1) days post-randomization.  If the subject was discharged, 
he/she should return to the clinic for the serum sodium collection.  In addition, the 
following procedures will be performed for any subjects terminating early:
1) A serum chemistry laboratory sample will be collected.
2) A blood sample for serum sodium testing will be collected.  (This blood draw 
can be combined with the chemistry panel as appropriate to minimize blood 
draws.)
3) A blood sample for PK analysis of tolvaptan will be collected at early 
termination (ET) only if ET occurs before the last scheduled PK assessment (ie, 
48 hours post-randomization for subjects continuing on tolvaptan).
Section 3.7.4.1 ADVERSE EVENTS
Changed Text:
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, 


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neurological symptoms, or other signs or symptoms suggestive of osmotic 
demyelination (see Section 5.3.1 for more detail).
Section 3.8.3 INDIVIDUAL SUBJECT
Changed Text:

The subject’s serum sodium increases by > 12 mmol/L in the 24-hour period 
following dosing
Section 5.3.1.1 RAPID CORRECTION OF SERUM SODIUM
Changed Text:
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.
Section 7.1.1 SAMPLE SIZE FOR EFFICACY
Changed Text:
A total of 80 70 randomized subjects will provide 90% power to detect a treatment 
difference of 4 mmol/L in change in serum sodium from randomization (at the end of 
Day 2/3 [Phase A]) to the end of Day 4/5 (2 days after randomization [Phase B]) 
using a 2-sided alpha of 0.05.  An SD of 5 in change of serum sodium was used for 
the sample size calculation.  After the end of treatment at Day 2/3, subjects will be 
randomized at a ratio of 1:1 to either continue treatment with tolvaptan for 
2 additional days (Late Withdrawal) or to discontinue tolvaptan treatment (Early 
Withdrawal).  Sample size re estimation will be conducted when 90% of the subjects 
finish (complete or discontinue) the trial.
Section 7.4.2.3 PHARMACOKINETIC PARAMETERS
Deleted Text:
The PK data of 81 adult subjects with a 30-mg tolvaptan dose will be included in the 
analysis to show the similarity for PK parameter estimates between adults and 
pediatrics.
Section 7.4.3 EXPLORATORY OUTCOME ANALYSIS
Added Text:
7.4.3 Exploratory Outcome Analysis


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Details will be provided in the statistical analysis plan.
Section 7.4.3.1 EFFICACY
Added Text:
7.4.3.1 Efficacy
The change in serum sodium concentration on Day 6 compared to Day 4 in 
nonresponders continuing on tolvaptan therapy will be analyzed using a paired 
Student’s t-test.
Section 7.4.3.2 SAFETY
Added Text:
7.4.3.2 Safety
Neurological examination data will be presented in the data listings.
Section 7.4.3.3 PHARMACODYNAMIC
Added Text:
7.4.3.3 Pharmacodynamic
The exploratory PD endpoints include:

In all subjects, 24-hour excretion of sodium, creatinine, and osmoles on Days 1 
and 2

24-hour sodium clearance
These endpoints will be analyzed as described in Section 6.2.
Section 7.4.4 INTERIM ANALYSIS
Changed Text:
7.4.3 7.4.4 Interim Analysis
It was recommended that an interim analysis should be conducted by the FDA to 
re-estimate the sample size when about 90% of the subjects had finished the trial, in 
order to re-evaluate the power of this protocol and provide sample size re-
estimation if needed.  In this case, this protocol would be a protocol of 2-stage 
adaptive design, in which the first stage would provide data for sample size re 
evaluation and the second stage would include all data collected after the first 
stage.  The final statistical test would combine data collected in both stages to 


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conclude the trial.  It was further recommended that the weighted Z statistic 
approach outlined in Cui et al 1999 should be used as the final statistical test, 
due to its flexibility and being able to maintain the type I error in any cases once 
the weights are prespecified.23
To identify the need of sample size increase, the conditional power (CP) would 
be examined under the current trend in the interim analysis.  Conditional power 
under the current trend is defined as the power of the trial of its planned sample 
size of 80 and the prespecified alpha of 0.05, under the assumption that the 
current trend observed at the interim analysis will continue to the end of the 
trial.  Under this assumption, there is no need to increase the sample size when 
the CP is high or low enough, since it is expected the trial would succeed if the 
CP is high enough and fail if the CP is low enough.  For this trial, the window for 
sample size increase is 50% CP < 80%.  Furthermore, this window is divided 
into 3 intervals [50%, 60%), [60%, 70%), and [70%, and 80), and the sample 
size increase (or sample size needed in the Stage 2) in these 3 intervals will be 
determined by the sample size increase when the CP is equal to 50%, 60%, and 
70%, respectively.  With a designed sample size of 80, an interim analysis at 70, 
and the use of the weighted Z statistics proposed in Cui et al 1999,23 in which 
nature weights of (70/80)1/2 and (10/80)1/2 are assigned to the Z statistics 
obtained in Stages 1 and 2, respectively, the estimated sample sizes based on 
these 3 intervals of CP are shown in Table 7.4.3 1.
Table 7.4.3-1 Condition Power
Condition Power
Sample Size for Stage 2
50% CP < 60%
168
60% CP < 70%
130
70% CP < 80%
96
Since the sample sizes needed for Stage 2 when CP falls in this window for 
sample size increase are very big and even bigger than the sample size planned 
for this trial (80), this adaptive design is very inefficient.  It would be much more 
efficient to allow this trial to run through its planned sample size (10 additional 
subjects) and, if necessary, to use the information collected to design a new trial.  
Thus, no adaptive sample size re-estimation will be designed in this trial, and no 
interim analysis in this trial will be conducted for the adaptive design.
The sample size re-estimation will assess the variability of change from 
randomization (end of Phase A) to end of Day 4/5 (Phase B) in serum sodium by 
using the pooled variance of the 2 treatment groups.  At the trial planning stage, 
an SD of 5 was used to detect a treatment difference of 4, resulting in a sample 
size of 70 with a 2-sided alpha of 0.05 and 90% power.  In case the variance ratio 
(equal to the observed pooled variance divided by 25, the square of 5 as an SD 
used in the sample size calculation) is 1, no sample size increase will be made, 
and the trial will proceed to finish enrollment of 70 randomized subjects.  In case 
the variance ratio is > 1, the sample size re-estimation will be equal to 70 


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multiplied by the variance ratio, then rounded up to the nearest even number.  
Table 7.4.3-1 provides an example of the sample size re-estimation under 
different variance ratios.
Table 7.4.3-1 Sample Size Re-estimation
Variance Ratio
Sample Size
1.1
78
1.2
84
1.3
92
1.4
78
1.5
106
Section 7.6.4 NEUROLOGICAL EXAMINATION
Deleted Text:
Neurological examination data will be presented in the listings.
Section 8.1 PACKAGING AND LABELING
Added Text:
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 or 50 kg who are taking moderate or 
potent inhibitors of CYP3A4, respectively.  Once available, the protocol will be 
amended to include the details of this formulation.
Section 14 REFERENCES
Added Text:
18
. Multicenter, randomized, double-blind, placebo-controlled, efficacy 
& safety study of the effects of titrated oral tolvaptan tablets in patients with 
hyponatremia. Otsuka CSR 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 CSR for Protocol 156-03-238, issued 
25 Jul 2006.
20
. A Randomized Double-Blind Study to Assess the Safety and 
Pharmacokinetics of Concomitant Administration of Orally Administered 
OPC-41061 Tablets and Ketoconazole in Healthy Adult Male and Female 
Volunteers. Otsuka Clinical Study Report for Protocol 156-98-201, issued 
07 Dec 2000, amended 15 Feb 2001, 28 May 2003, and 03 Mar 2004.


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Deleted Text:
23 Cui L, Hung HMJ, Wang SJ. Modification of sample size in group sequential 
clinical trials. Biometrics. 1999;55:1551-62.
Appendix 1 NAMES OF SPONSOR PERSONNEL
Replaced table:
Country
Safety Fax Numbers
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Protocol 156-08-276
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Protocol 156-08-276
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Amendment Number:
2
Issue Date:
19 May 2014
PURPOSE:

To increase the consistency of this protocol with other tolvaptan pediatric 
hyponatremia protocols

To add neurocognitive and quality-of-life assessments as exploratory endpoints 

To clarify study design, procedures, and assessments

To better define study phases and associated visits

To provide greater detail about clinical laboratory tests

To add Tanner staging to the assessments performed during the physical 
examination

To better define completers and stopping rules

To incorporate newly 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 as much consistency in data collection and to allow for data to 
be generated that could be synthesized and analyzed across studies.  
SECTIONAL REVISIONS:
Location:
Old Text:
New Text:
Title Page:
Medical Director: 
 
 
 
 
 
 
Date of Amendment 2: 19 May 2014
Protocol
Synopsis/
Secondary 
Objective:
To assess the pharmacokinetics (PK) of 
tolvaptan and the effect on fluid balance in 
children and adolescent subjects with 
euvolemic or hypervolemic hyponatremia.
To assess tolvaptan’s pharmacokinetics 
(PK) and its effect on fluid balance in 
children and adolescent subjects with 
euvolemic or hypervolemic hyponatremia.
Trial Design:
Subjects will undergo a treatment phase 
(2 to 5 days of tolvaptan) and a follow-up 
phase post-randomization of 14 days.
Phase A (Treatment Phase):  All subjects 
will initially receive tolvaptan once daily for 
the first 2 days.  If a subject has not reached 
the desired sodium target improvement per 
the investigator’s judgment (ie, the subject 
is a nonresponder) after Day 2 of tolvaptan 
The trial will be conducted in two stages. 
The first stage will be conducted using the 
available tablet formulation of tolvaptan 
whereas the second stage will expand to the 
use of a suspension once that formulation 
becomes available….
Subjects will be required to be in a hospital 
setting during initiation and titration of 


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administration (post 2 doses), a third day of 
treatment is permitted.
At the end of Day 2 (optionally Day 3), 
subjects who are responders will be 
randomized to either the Early or Late 
Withdrawal group.  Responders will be 
defined as those subjects who achieve an 
increase in serum sodium by 4 mmol/L.  
Early or Late Withdrawal assignment will 
be stratified by age 
 
), serum sodium response 
 
, and underlying etiology 
of hyponatremia.  If the subject remains a 
nonresponder to tolvaptan at the end of Day 
3, the investigator is permitted to continue 
tolvaptan for 2 additional days at the highest 
dose or to discontinue tolvaptan and treat 
the subject per the investigator’s preferred 
standard of care.
Phase B (Randomization Phase):  Subjects 
who are randomized to the Late Withdrawal 
group and nonresponders continuing 
treatment after Day 3 will continue 
treatment with tolvaptan for 2 additional 
days.  Subjects who are randomized to the 
Early Withdrawal group and nonresponders
discontinuing treatment after Day 3 will 
discontinue tolvaptan treatment 
immediately after randomization.
Nonresponders will be treated per the 
investigator’s preferred standard of care 
during Days 3/4 and 4/5 (treatment day is 
dependent upon the number of doses that a 
subject receives during Phase A).
Those subjects whose serum sodium 
declines by 4 mmol/L or whose overall 
clinical condition requires further treatment 
to increase serum sodium will be treated per 
the investigator’s preferred standard of care. 
Any intervention intended to raise serum 
sodium during the first 48 hours of the 
Early Withdrawal phase (including fluid 
restriction) will be defined as rescue 
therapy; the subject will be considered to 
have reached their clinical endpoint, and 
their data will be censored from that time 
forward.
All subjects will have serum sodium 
measured at 12, 24, 36, and 48 (4) hours 
tolvaptan.
Overall, in this trial, subjects will undergo 
treatment (2 to 5 days of tolvaptan among 2 
treatment phases) and a post-last dose 
follow-up phase of 14 days.
Treatment Phase A
After screening, all subjects will initially 
receive tolvaptan once daily for 2 days.  If 
the desired serum sodium level target 
improvement is not reached after Day 2 of 
tolvaptan administration (post 2 doses), a 
third day (Day 2a) of treatment is required.  
At the end of Day 2 (or 2a), subjects will be 
assessed for a serum sodium level change of 
4 mEq/L (mmol/L). At that time, subjects 
who are responders will be randomized to 
either the Early Withdrawal group or Late 
Withdrawal group.  Responders are defined 
as those subjects who achieve an increase in 
serum sodium concentration of 
4 mEq/L (mmol/L); nonresponders are 
defined as subjects who do not achieve an 
increase in serum sodium concentration of 
4 mEq/L (mmol/L).
Treatment Phase B  
Responders
Responders from Treatment Phase A will be 
randomized to either the:

Late Withdrawal group - subjects 
continue tolvaptan treatment on Days 3 
and 4

Early Withdrawal group - subjects do 
not receive additional tolvaptan 
treatment on Days 3 and 4.
Randomization will include stratification by 
age 
, 
serum sodium response 
 
, and underlying etiology of 
hyponatremia.  
Those subjects whose serum sodium level 
declines by 4 mEq/L (mmol/L), or whose 
overall clinical condition requires further 
treatment to increase serum sodium level, 
will be treated per the investigator’s 
preferred standard of care.  Any 
intervention intended to raise serum sodium 
level during the first 48 hours of the Early 
Withdrawal phase (including fluid 
restriction) will be defined as rescue 
therapy.  Subjects who receive rescue 


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post-randomization.  Serum sodium 
assessment time points for nonresponders 
will follow the same schedule, but the 
values will be reported separately from the 
primary efficacy analysis.  For analysis 
purposes, these assessments for 
nonresponders will be referred to as 
“post-randomization.”
Phase C (Follow-up Phase):  All subjects 
will be monitored and treated as clinically 
warranted per the investigator’s preferred 
standard of care for up to 3 additional days 
after the last dose of tolvaptan (note:  the 
Early Withdrawal group should be 
monitored for the first 48 hours post-last 
dose).  All subjects will have an additional 
serum sodium measurement at 
72 (4) hours post-randomization and 
7 (1) days post-randomization.  A final 
safety follow-up telephone contact/visit will 
be performed 14 (+ 2) days 
post-randomization.
Pharmacokinetic samples will be obtained 
on Day 1 (Phase A) and, for tolvaptan-
treated subjects, at 24 and 48 hours 
post-randomization in Phase B.  The PK 
profiles will be evaluated on an ongoing 
basis to determine the variability between 
subjects.  Based on the findings, PK 
sampling will continue for as long as 
necessary to establish suitable estimates of 
clearance with a 90% confidence interval 
(CI) similar to that observed in the adult 
populations.  Once these estimates are 
achieved, sampling will be discontinued in 
subsequent subjects in order to minimize 
blood draws in this population.
Subjects will be required to be in the 
hospital during initiation or up-titration of 
administration of tolvaptan.  If a subject is 
in the withdrawal phase or is not expected 
to receive a higher dose of tolvaptan, 
continued administration can be done 
outside of the hospital setting.  Follow-up 
for all subjects 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.
therapy will be considered to have reached 
their clinical endpoint, and their data will be 
censored from that time forward.
Nonresponders
If the subject remains a nonresponder at the 
end of Day 2 (or 2a), the investigator 
decides to either (a) continue tolvaptan for 2 
additional days, or (b) discontinue tolvaptan 
and treat the subject per the investigator’s 
preferred standard of care during Days 3 and 
4. Subjects will continue to follow 
scheduled assessments regardless of 
treatment.
All Subjects
All subjects will have serum sodium levels 
measured at 8, 12, and 24 hours post-first 
dose and thereafter every 12 hours through 
completion of Treatment Phase B.  
Follow-up Phase C  
All subjects will have an additional serum 
sodium assessment at 72 (4) hours post-
last dose and 7 (1) days post-last dose.  A 
final safety follow-up telephone 
contact/visit will be performed 14 (+ 2) 
days post-last dose.
Pharmacokinetic Sampling
Blood samples for pharmacokinetic (PK) 
analysis will be obtained at 2 and 8 hours 
post-first dose, and at trough on Days 2, 3, 4 
and 5 for all subjects when dosed with 
tolvaptan on Days 1, 2, 3, and 4, 
respectively, regardless of responder status.   
PK profiles will be evaluated on an ongoing 
basis to determine variability among 
subjects.  Based on the findings, PK 
sampling will continue for as long as 
necessary to establish suitable estimates of 
clearance with a 90% confidence interval 
(CI), similar to that observed in adult 
subject populations.  Once these estimates 
are achieved, sampling will be discontinued 
in subsequent subjects in order to minimize 
blood draws in this pediatric population.
Subject 
Population:
This trial will include up to 100 male and 
female subjects aged 4 weeks (or 44 
This trial will include up to 100 male and 
female subjects aged 4 weeks (or 44 


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weeks adjusted gestational age for 
premature births) to < 18 years who have 
been diagnosed with euvolemic or 
hypervolemic hyponatremia 
(< 130 mmol/L) that persists despite initial 
standard background therapy (including 
fluid restriction and excluding a vasopressin 
antagonist).  It is expected that 70 subjects 
will have a serum sodium increase of 4 
mmol/L (ie, responders).
Subjects with euvolemic or hypervolemic 
hyponatremia eligible to be screened for 
participation in this trial 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 inappropriate secretion of 
antidiuretic hormone (SIADH).  Subjects 
with acute hyponatremia or hyponatremia 
expected to resolve spontaneously will be 
excluded from the trial…. 
Seventy randomized subjects will provide 
90% power to detect a treatment difference 
of 4 mmol/L in change in serum sodium 
from randomization (at the end of Day 2/3 
[Phase A]) to the end of Day 4/5 (2 days 
after randomization [Phase B]).  
 
 
 
.  
Subjects who are defined as responders will 
be further stratified by the magnitude of 
serum sodium response to tolvaptan 
 
 and underlying etiology of 
hyponatremia.
All subjects 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 that it remains 
persistent below this threshold prior to 
intended treatment initiation.
weeks adjusted gestational age) to < 18 
years who have been diagnosed with 
euvolemic or hypervolemic hyponatremia 
(< 130 mEq/L [mmol/L]) that persists 
despite initial standard background therapy 
(including fluid restriction and excluding a 
vasopressin antagonist). Age groups will be 
enrolled such that 50% of these subjects 
will be < 10 years old and at least 25% of 
subjects < 6 years old.  
Subjects with acute hyponatremia or 
hyponatremia expected to resolve 
spontaneously will be excluded from the 
trial…. 
Inclusion/ 
Exclusion 
Criteria:
Key inclusion criteria:

Male and female subjects 4 weeks (or 
44 weeks adjusted gestational age for 
premature births) to < 18 years old…

Persistent euvolemic or hypervolemic 
Key inclusion criteria:

Male and female subjects 4 weeks (or 
44 weeks adjusted gestational age) to 
< 18 years old…

Persistent euvolemic or hypervolemic 


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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
Key exclusion criteria:

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 < 90 mmHg or pulse > 
120 bpm, then volume status should be 
specifically clinically assessed to rule 
out volume depletion

Has serum sodium < 120 mmol/L, with 
or without associated neurologic 
impairment (ie, symptoms such as 
apathy, confusion, or seizures)

Has a history or current diagnosis of 
nephrotic syndrome

Has transient hyponatremia likely to 
resolve (eg, head trauma or post-
operative state)

Has hyperkalemia defined as serum 
potassium above the upper limit of 
normal (ULN) for the appropriate 
pediatric age range

Has estimated glomerular filtration rate 
(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)

Has severe or acute neurological
symptoms requiring other intervention 
(eg, hyperemesis, obtundation, seizures)

Has had treatment for hyponatremia 
with:

Has psychogenic polydipsia (subjects 
with other psychiatric illness may be 
included per medical monitor approval)

Has uncontrolled diabetes mellitus 
defined as fasting glucose > 300 mg/dL 
(16.7 mmol/L)

Has Screening liver function values > 3 
ULN
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 2-4 hours prior to the 
first dose of tolvaptan
Key exclusion criteria:

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, then 
volume status should be specifically 
clinically assessed to rule out volume 
depletion

Has serum sodium level < 120 mEq/L 
(mmol/L), with or without associated 
neurologic impairment (ie, symptoms 
such as apathy, confusion, or seizures)

Has estimated glomerular filtration rate 
(eGFR) < 30 mL/min/1.73 m2

Has had treatment for hyponatremia 
with:

Uncontrolled diabetes mellitus defined 
as fasting glucose > 300 mg/dL (16.7 
mEq/L [mmol/L])

Screening liver function values 
>3ULN

Deficient coagulation (eg, cirrhotic at 
risk of gastrointestinal [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 medications 
known to increase bleeding risk


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
Has deficient coagulation (eg, cirrhotic 
at risk of gastrointestinal [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

Has hyponatremia due to the result of 
any medication that can safely be 
withdrawn (eg, thiazide diuretics)
Has hyponatremia (eg, hyponatremia in the 
setting of adrenal insufficiency, untreated 
hypothyroidism, or hypotonic fluid 
administration) that is most appropriately 
corrected by alternative therapies
Investigational 
Medicinal 
Product, Dose, 
Formulation, 
Mode of 
Administration
…Upon the availability of a liquid 
formulation, the protocol will be amended 
to reflect additional dosing options.
…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, weighing < 10 
kg, or who cannot safely swallow the 
tablet will be excluded until the 
availability of a liquid formulation.  
Dosing information will be available at 
that time.
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 
exceeding 12mmol/L/24 hours.
At the end of Day 2 (optionally Day 3 
[Phase A]), subjects with a serum sodium 
increase of 4 mmol/L will be randomized 
to either continue treatment with tolvaptan 
for 2 additional days (Late Withdrawal) or 
to discontinue tolvaptan treatment (Early 
Withdrawal).  Early or Late Withdrawal 
assignment will be stratified by age 
(
, serum 
….Upon the availability of an oral 
suspension formulation, the protocol will be 
amended to reflect additional dosing 
options.
….Up-titration of tolvaptan doses will be 
based on serum sodium levels at > 20 hours 
following initiation of therapy and at >20 
hours following each additional dose; a 
change in serum sodium 4 mEq/L 
(mmol/L) from baseline should warrant 
up-titration, which is limited to no more 
than twice the previous dose.

Subjects < 2 years of age, weighing < 10 
kg, or who cannot safely swallow the 
tablet will be excluded until the 
availability of a suspension formulation.  
The subjects will continue dosing according 
to a titration scheme targeting a final serum 
sodium concentration between 135 and 140 
mEq/L (mmol/L).  Titration will ideally 
achieve a change in serum sodium 
concentration of at least 4 to 8 mEq/L 
(mmol/L)/24 hours but not exceeding 
.


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sodium response 
, and 
underlying etiology of hyponatremia.  
Nonresponders will be allowed to be treated 
with tolvaptan for 2 additional days at the 
highest dose or to discontinue tolvaptan and 
be treated per the investigator’s preferred 
standard of care.
Trial 
Assessments:
Pharmacokinetic/pharmacodynamic:

Blood sampling for tolvaptan plasma 
concentrations

Fluid balance

Urine output and urine chemistry
Safety:

Physical examinations, including body 
weight

Neurological examinations
Screening/Baseline:

Clinical laboratory tests (hematology, 
coagulation, chemistry, urinalysis)

Electrocardiogram

Medical and hyponatremia history

Thyroid-stimulating hormone and 
cortisol tests

Plasma osmolality, fractional excretion 
of sodium, and fractional excretion of 
urate

Alcohol and drug screen

Pregnancy test
Pharmacokinetic/pharmacodynamic:

Blood sampling for tolvaptan and 
metabolite plasma concentrations

Fluid intake

Urine output 

Urine chemistry
Safety:

Physical examinations, including body 
weight and neurological examinations
Criteria for 
Evaluation:
Primary Endpoints:
Efficacy:

For subjects with serum sodium 
increases of 4 mmol/L (ie, 
responders), change in serum sodium 
concentration from randomization (at 
the end of Day 2/3 [end of Phase A]) to 
the end of Day 4/5 (Phase B) for Early 
compared to Late Withdrawal groups
Secondary Endpoints:
Efficacy:

For all subjects, change in serum 
sodium concentration at the end of 
Day 2/3 from baseline in Phase A
Safety:

Percentage of subjects with overly rapid 
increase in serum sodium 
 

Percentage of subjects requiring rescue 
medication during Phase A and Phase B 
of the trial

Change in serum sodium from 24 hours 
Primary Efficacy Endpoint

For subjects with serum sodium level 
increases of 4 mEq/L (mmol/L) (ie, 
responders), change in serum sodium 
concentration from Day 2 (or 2a) at the 
end of Treatment Phase A to the end of 
Treatment Phase B for Early compared 
to Late Withdrawal groups.
Key Secondary Efficacy Endpoint

For all subjects, the key secondary 
endpoint is the change in serum sodium 
concentration at the end of Day 2 (or 
2a) in Treatment Phase A from 
baseline.  
Other Secondary Endpoints
Safety:

Percentage of subjects with overly rapid 
increase in serum sodium level 
 
 
)


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post-last dose to 14 days post-
randomization

Vital signs, blood pressure, clinical 
laboratory tests, and body weight
Pharmacokinetic:

On Day 1, tolvaptan maximum (peak) 
plasma concentration (Cmax), time to 
maximum (peak) plasma concentration 
(tmax), and area under the 
concentration-time curve from time 
zero to 24 hours (AUC0-24h)
Pharmacodynamic:

Fluid intake, urine output, and fluid 
balance (intake −output) every 6 hours 
on Days 1 and 2 (Phase A)
Exploratory Endpoints:
Efficacy:

In nonresponders continuing on 
tolvaptan therapy, change in trough 
serum sodium concentration on Day 6 
compared to Day 4
Safety:

Neurological examinations
Pharmacodynamic:

In all subjects, 24-hour excretion of 
sodium, creatinine, and osmoles on 
Days 1 and 2

24-hour sodium clearance

Change in serum sodium level from 24 
hours post-last dose to 7 days post-last 
dose

Percentage of subjects requiring rescue 
therapy (other than fluid restriction) 
during Treatment Phase A and 
Treatment Phase B 

Percentage of subjects requiring fluid 
restriction during Treatment Phase A 
and Treatment Phase B 

Vital signs, blood pressure, clinical 
laboratory tests, body weight, and 
neurological examinations
Pharmacokinetic:

On Day 1 in Treatment Phase A, 
tolvaptan maximum (peak) plasma 
concentration (Cmax), time to maximum 
(peak) plasma concentration (tmax), and 
area under the concentration-time curve 
from time zero to 24 hours (AUC0-24h)
Pharmacodynamic:

Fluid intake, urine output, and fluid 
balance (intake minus output) every 6 
hours on Days 1 and 2  in Treatment 
Phase A
Exploratory Endpoints

Efficacy will be assessed in 
nonresponders continuing on tolvaptan 
therapy by change from baseline in 
serum sodium concentration at the end 
of Treatment Phase B compared to the 
end of Treatment Phase A. 

In all subjects, 24-hour excretion of 
sodium, creatinine, and osmolality on 
Days 1 and 2

24-hour sodium clearance on Day 1

Neurocognition test battery 

Quality of life (QoL) assessments
List of 
Abbreviations 
and Definitions 
of Terms
Abbreviation
Definition
BUN
Blood urea nitrogen
FENa
Fractional excretion of 
sodium
FE urate
Fractional excretion of 
urate
HF
Heart failure
SAP
Statistical analysis plan
1.2 Clinical 
Data
Tolvaptan was approved in adults by the US 
FDA, in 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 
Tolvaptan is approved for (a) the treatment 
of specific forms of hyponatremia in adults 
by the European Medicines Agency (EMA), 
United States (US) Food and Drug 
Administration (FDA), and the regulatory 
authorities of 9 other countries, and (b) for 
volume overload in heart failure (HF) by the 
Japanese Ministry of Health, Labour, and 


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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.
Welfare.  Tolvaptan is currently being 
investigated for the treatment of autosomal 
dominant polycystic kidney disease 
(ADPKD) and 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 were ongoing.  
More information is available in the IB.1
2.1 Trial 
Rationale
The purpose of this trial … various 
etiologies.  … As the primary physiological 
effect of tolvaptan…
The proposed population size of 100 
subjects should provide 70 responders, …
The purpose of this trial … HF, 
hepatocellular disease (including cirrhosis), 
and SIADH/other.  … As the primary 
pharmacodynamic effect of tolvaptan…
The proposed population size of 100 
subjects is expected to yield 70 subjects 
who respond to tolvaptan (henceforth 
termed “responders”), …
2.2.2 Secondary 
Objective
The secondary objective is to assess the PK 
of tolvaptan and the effect on fluid balance 
in children and adolescent subjects with 
euvolemic or hypervolemic hyponatremia.
The key secondary objective is to assess the 
PK of tolvaptan and the effect on fluid 
balance in children and adolescent subjects 
with euvolemic or hypervolemic 
hyponatremia.
3 Trial Design
3.1 Type/Design of Trial
See Figure 3.1-1 for a schematic of the trial 
design.
This will be an open-label, multicenter, 
multiple-dose, randomized withdrawal, 
parallel-group trial of tolvaptan in children 
and adolescent subjects hospitalized with 
euvolemic or hypervolemic hyponatremia.
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 participation in this trial.  Subjects who 
demonstrate prior resistance to vasopressin 
antagonist therapy will be excluded.  All 
potential subjects must also be deemed by 
the investigator as likely to benefit from a 
therapy that raises serum sodium levels.
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 this protocol, persistent 
hyponatremia will be defined as serum 
sodium assessments < 130 mmol/L 
documented as present for at least 48 hours.  
3.1 Type of Trial
This is an open-label, multicenter, multiple-
dose, randomized withdrawal, 
parallel-group trial of tolvaptan in children 
and adolescents hospitalized with chronic 
euvolemic or hypervolemic hyponatremia 
(serum sodium < 130 mEq/L [mmol/L]) 
persisting despite initial standard therapy.  
A schematic of the trial design is provided 
in Figure 3.1-1.
This is the first clinical trial of tolvaptan in 
a pediatric population, and the majority of 
subjects may require only short-term 
treatment of hyponatremia, however some 
subjects may require prolonged treatment 
and additional follow-up information on 
their response to tolvaptan may be desired 
to better understand its long-term safety 
profile in this pediatric population.  Hence, 
all subjects (responders and nonresponders) 
who complete this trial will be eligible for 
enrollment into an extension trial 
(156-11-294) to continue receiving 
tolvaptan, as clinically appropriate, until it 
is approved and available locally.  If 
eligible, subjects could continue therapy 
with tolvaptan in that trial after completing 
the 14 (+2) day Follow-up Visit and 
completion of this trial.  (The extension 
study will also provide long-term post-
treatment safety follow-up information for a 


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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.
As stated above, all 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 status for each 
subject using diagnostic tests (eg, fractional 
excretion of sodium [FeNa], fractional 
excretion of urate [Fe urate], urine 
osmolality, plasma osmolality) employed in 
the usual clinical course of care.
Additionally, the following considerations 
should be noted per underlying etiology:

Subjects diagnosed with hyponatremia 
secondary to SIADH will be evaluated 
specifically to ensure appropriate 
volume status.  Hypovolemic states are 
not compatible with tolvaptan 
administration.  Plasma and urine 
sodium, potassium, creatinine, and uric 
acid will be assessed in order to 
calculate and evaluate the FeNa and the 
Fe urate prior to dosing to ensure safety 
of tolvaptan administration.

Subjects diagnosed with hyponatremia 
secondary to CHF are required to have 
a definitive diagnosis of CHF by a 
cardiologist and must have any diuretic 
regimen evaluated to ensure it is not 
contraindicated with tolvaptan 
administration.

Subjects diagnosed with hyponatremia 
due to hepatocellular disease must have 
stable disease.

All subjects must meet appropriate 
acute kidney injury (AKI) criteria per 
the exclusion criteria.
The first dose of trial medication will be 
administered upon successful completion of 
minimum of 6 months.)
The trial will be conducted in two stages. 
The first stage will be conducted using the 
available tablet formulation of tolvaptan 
whereas the second stage will expand to the 
use of a suspension once that formulation 
becomes available.


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all screening procedures.
Subjects will undergo a treatment phase (2 
to 5 days of tolvaptan) and a follow-up 
phase post-randomization of 14 days.
Phase A (Treatment Phase):  All subjects 
will initially receive tolvaptan once daily for 
the first 2 days.  If a subject has not reached 
the desired sodium target improvement per 
the investigator’s judgment (ie, the subject 
is a nonresponder) after Day 2 of tolvaptan 
administration (post 2 doses), a third day of 
treatment is permitted.
At the end of Day 2 (optionally Day 3), 
subjects who are responders will be 
randomized to either the Early or Late 
Withdrawal group.  Responders will be 
defined as those subjects who achieve an 
increase in serum sodium by 4 mmol/L.  
Randomized withdrawal assignment will be 
stratified by age 
 
, by serum sodium response 
 
, and by underlying 
etiology of hyponatremia.  If the subject 
remains a nonresponder to tolvaptan at the 
end of Day 3, the investigator is permitted 
to continue tolvaptan for 2 additional days 
at the highest dose or to discontinue 
tolvaptan and treat the subject per the 
investigator’s preferred standard of care.
Phase B (Randomization Phase):  Subjects 
who are randomized to the Late Withdrawal 
group and nonresponders continuing 
treatment after Day 3 will continue 
treatment with tolvaptan for 2 additional 
days.  Subjects who are randomized to the 
Early Withdrawal group and nonresponders 
discontinuing treatment after Day 3 will 
discontinue tolvaptan treatment 
immediately after randomization.
Nonresponders will be treated per the 
investigator’s preferred standard of 
care during Days 3/4 and 4/5 
(treatment day is dependent upon the 
number of doses that a subject 
receives during Phase A).
Subjects who are randomized to the Early 
Withdrawal group will initially be observed 
to determine whether additional intervention 
is required to maintain appropriate serum 
sodium levels.  Those subjects whose serum 
sodium declines by 4 mmol/L or whose 


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overall clinical condition requires further 
treatment to increase serum sodium will be 
treated per the investigator’s preferred 
standard of care.  Any intervention intended 
to raise serum sodium during the first 48 
hours of the Early Withdrawal phase 
(including fluid restriction) will be defined 
as rescue therapy; the subject will be 
considered to have reached their clinical 
endpoint, and their data will be censored 
from that time forward.
All subjects will have serum sodium 
measured at 12, 24, 36, and 48 (4) hours 
post-randomization.  Serum sodium 
assessment time points for nonresponders 
will follow the same schedule, but the 
values will be reported separately from the 
primary efficacy analysis.  For analysis 
purposes, these assessments for 
nonresponders will be referred to as “post-
randomization.”
Phase C (Follow-up Phase):  All subjects 
will be monitored and treated as clinically 
warranted per the investigator’s preferred 
standard of care for up to 3 additional days 
after the last dose of tolvaptan (note:  the 
Early Withdrawal group should be 
monitored for the first 48 hours post-last 
dose).  All subjects will have an additional 
serum sodium measurement at 
72 (4) hours post-randomization and 
7 (1) days post-randomization.  A final 
safety follow-up telephone contact/visit will 
be performed 14 (+ 2) days 
post-randomization.
Pharmacokinetic samples will be obtained 
on Day 1 (Phase A) and, for tolvaptan-
treated subjects, at 24 and 48 hours post-
randomization in Phase B.  The PK profiles 
will be evaluated on an ongoing basis to 
determine the variability between subjects.  
Based on the findings, PK sampling will 
continue for as long as necessary to 
establish suitable estimates of clearance 
with a 90% confidence interval (CI) similar 
to that observed in the adult populations.  
Once these estimates are achieved, sampling 
will be discontinued in subsequent subjects 
in order to minimize blood draws in this 
population.


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Subjects will be required to be in the 
hospital during initiation or up-titration of 
the administration of tolvaptan.  If a subject 
is in the withdrawal phase or is not expected 
to receive a higher dose of tolvaptan, 
continued administration can be done 
outside of the hospital setting.  Follow-up 
for all subjects 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.
Subjects who do not improve on tolvaptan 
may receive rescue therapy per the 
investigator’s judgment (see Section 3.2.2).  
These subjects will be withdrawn from trial 
treatment and will continue to Phase C to be 
followed as per protocol.
While understanding that the majority of 
hyponatremia in this patient population may 
only require short-term treatment, it is 
recognized that some subjects may require 
prolonged treatment.  Hence, all subjects 
(responders and nonresponders) who 
complete this trial may be eligible to be 
enrolled for an additional (planned) open-
label use trial (156-11-294) to enable 
continued use of tolvaptan or to be 
clinically followed.  If deemed eligible, 
these subjects could continue therapy with 
tolvaptan after the 14-day Follow-up Visit 
and completing this trial.


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3.1: Type of Trial
Figure 3.1-1 Trial Design Schematic


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Figure 3.1: Type of Trial
Treatment Phase A
Eligibility 
determined
Screening/
Baseline 
Visit
Days 
-2 to -1
Day 1
All Eligible 
Subjects
Day 2
All Eligible 
Subjects
Day 2a
OPTIONAL
Follow-up
72 (± 4) 
hours
post-last 
dose
Follow-up
7 (± 1) days 
post-last 
dose
Follow-up
14 (+ 2) days 
post-last 
dose
Serum Sodium
< 4 mEq/L = 
Nonresponder
Serum Sodium
≥4 mEq/L = 
Responder
Day 3
Study Drug
Day 4
Study Drug
EARLY WITHDRAWAL
LATE WITHDRAWAL
RANDOM-
IZATION
PI
DECISION
Day 3
Study Drug
Day 4
Study Drug
Note:  Subjects will be 
eligible to rollover into 
Trial 156-11-294 after the 
14-day Follow-up Visit
Day 3
Standard 
of Care
Day 4
Standard 
of Care
Day 3
No Study 
Treatment
Day 4
No Study 
Treatment
RESPONDER
Stratified Randomization to 
EARLY OR LATE WITHDRAWAL
NONRESPONDER
Assess 
≥4 mEq/L 
change
mEq/L = mmol/L
Treatment Phase B
Follow-up Phase C
Day 5
No Study 
Treatment
Day 5
No Study 
Treatment
X
X
Figure 3.1-1 Trial Design Schematic


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Subjects must be 2 years of age and 
weigh 10 kg until development of a liquid 
formulation is complete.
3.2 Treatments
Tolvaptan will be administered once daily 
orally, preferably in the morning hours, 
with a dose proportional amount of water.  
The acceptability and palatability of 
tolvaptan tablets will be recorded on the 
case report form (CRF).  Doses of 15 mg 
tolvaptan will be given with 240 mL of 
water…
…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 
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 who cannot take an oral tablet are 
currently excluded due to their inability to 
safely swallow the spray-dried tablet.  
Subjects weighing < 10 kg are also 
3.1.1 Trial Phases
Screening should be performed on Days −2 
and −1 to confirm eligibility, followed by 
the 3 trial phases described in Section 3.7.1.
3.1.1.1 Treatment Phase A
All subjects will initially receive tolvaptan 
once daily on Days 1 and 2.  If a subject’s 
serum sodium level has not increased by at 
least 4 mEq/L (mmol/L) by Day 2, an 
additional day of treatment is required and 
is referred to as Day 2a.  If subjects achieve 
an increase in serum sodium concentration 
of 4 mEq/L (mmol/L) on Day 2 (or 2a) 
they will be defined as responders.  If 
subjects do not achieve an increase in 
serum sodium concentration of 4 mEq/L 
(mmol/L) on Day 2 (or 2a) they will be 
defined as nonresponders.
3.1.1.2 Treatment Phase B
On Day 3 responders will be randomized 
(Section 3.1.1.2.1) to either the Early 
Withdrawal group or the Late Withdrawal 
group. Nonresponders will not be 
randomized.
For nonresponders from Treatment Phase 
A, the investigator will determine if the 
subject is to either: 

Continue treatment with study drug or 

Prescribe treatment per local standard of 
care for Days 3 and 4.
3.1.1.2.1 Randomization
Responders will be randomized to either:  

Late Withdrawal group - subjects 
continue tolvaptan treatment on Days 3 
and 4

Early Withdrawal group - subjects do 
not receive additional tolvaptan 
treatment on Days 3 and 4.
Randomization will be stratified by age (< 
), serum 
sodium response 
 
, and underlying hyponatremia 
etiology 
 
 
. 
Subjects randomized to the Early 
Withdrawal group will be observed to 
determine whether additional intervention 
is required to maintain appropriate serum 
sodium levels.  Subjects whose serum 
sodium declines by 4 mEq/L (mmol/L) or 


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excluded as that weight has not been 
studied in previous PK trials and, therefore, 
the dose of tolvaptan being delivered is not 
confirmed.  To support the enrollment of 
these subjects, an age and weight 
appropriate suspension formulation is being 
developed.  Once available, the protocol 
will be amended to include the formulation.
Table 3.2-1 presents starting doses of 
tolvaptan (15, 7.5, or 3.75 mg) when 
adjusted for body weight.
Consequently, the maximal starting dose 
for subjects weighing > 50 kg is slightly 
less than 0.30 mg/kg; starting doses for 
subjects weighing 20 to 50 kg, inclusive, 
range from 0.38 to 0.15 mg/kg; starting 
doses for subjects weighing 10 to < 20 kg 
range from 0.375 mg/kg to slightly greater 
than 0.19 mg/kg.  Therefore, the maximal 
starting doses planned for this pediatric trial 
are in the range previously used in adult 
hyponatremic subjects.
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)….
The subjects will continue dosing according 
to a titration scheme (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 
exceeding 12 mmol/L/24 hours.
At the end of Day 2 (optionally Day 3 
[Phase A]), subjects with a serum sodium 
increase of 4 mmol/L will be randomized 
to either continue treatment with tolvaptan 
for 2 additional days (Late Withdrawal) or 
to discontinue tolvaptan treatment (Early 
Withdrawal).  Early or Late Withdrawal 
assignment will be stratified by the ages of 
, serum 
sodium response 
, and 
underlying etiology of hyponatremia.
Subjects with serum sodium response of < 
4 mmol/L may continue on tolvaptan 
therapy for 2 additional days at their 
highest dose or may be withdrawn from 
tolvaptan to be treated per the investigator’s 
preferred standard of care.
whose overall clinical condition requires 
further treatment to raise serum sodium 
levels should be treated per local standard 
of care.  Any intervention intended to raise 
serum sodium concentration during the first 
48 hours of the Early Withdrawal phase 
(including fluid restriction) will be defined 
as rescue therapy.  Subjects receiving 
rescue therapy will be considered to have 
reached their clinical endpoint, and their 
data will be censored from that time 
forward.
3.1.1.3 Follow-up Phase C
All subjects will have an additional serum 
sodium measurement at 72 (4) hours 
post-last dose and 7 (1) days post-last 
dose.  A final safety follow-up telephone 
contact/visit will be performed 14 (+ 2) 
days post-last dose.
3.2.1 Tablet Formulation
Tolvaptan tablets will be administered 
orally once daily, 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…
The maximum starting doses, by weight, 
for subjects are shown in Table 2.1.1-1 and 
are within the range previously used in 
trials involving adult hyponatremic 
subjects.
The palatability of tolvaptan tablets will be 
assessed.  
3.2.2 Suspension Formulation
Additional information on the proposed 
suspension formulation of tolvaptan 
(currently in development) will be added to 
the protocol in an amendment when 
available. Until that time, subjects < 2 years 
of age or weighing < 10 kg and those 
unable to swallow tablets, are excluded 
from the trial.
3.2.3 Dosing Guidelines
…Titration of tolvaptan doses can occur 
once daily 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.  
Up-titration is limited to no more than 
twice the previous dose.


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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, then the dose of tolvaptan 
should be held and the medical monitor 
should be called.  If serum sodium 
changes by 4mmol/L/24 hours and the 
subject is still below the therapeutic 
target for serum sodium (135mmol/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 and will continue to Phase C 
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.
3.2.1.1 Rescue Therapy
Subjects with worsening hyponatremia 
symptoms during the trial may receive 
rescue therapy. ….commercial vaptans, or 
any treatment intended to raise the level of 
serum sodium.
Subjects who are randomized to the Early 
Withdrawal group will initially be observed 
to determine whether additional 
intervention is required to maintain 
appropriate serum sodium levels.  Those 
subjects whose serum sodium declines by 
4 mmol/L or whose overall clinical 
condition requires further treatment to 
increase serum sodium will be treated per 
the investigator’s preferred standard of 
care.  Any intervention intended to raise 
serum sodium during the first 48 hours of 
the Early Withdrawal phase (including fluid 

Subjects < 2 years of age or weighing < 
10 kg are excluded until an oral 
suspension formulation is available.  

Subjects 2 years of age and weighing 
10 to < 20 kg will receive a 3.75 mg 
tablet on Day 1 with possible 
up-titration to 7.5 mg and 15 mg tablet 
doses.

Subjects weighing 20 to 50 kg, 
inclusive, will receive a 7.5 mg tablet 
on Day 1 with possible up-titration to 
15 mg and 30 mg tablet doses.

Subjects weighing > 50 kg will receive 
a 15 mg tablet on Day 1 with possible 
up-titration to 30 mg and 60 mg tablet 
doses.
For subjects weighing 20 kg and taking 
moderate inhibitors of CYP3A4, one half of 
the standard dose will be used (3.75 or 7.5 
mg, by weight)….
Following their initial tolvaptan dose in the 
trial subjects will continue dosing 
according to the titration scheme (see
Section 3.2.4), targeting a final serum 
sodium concentration between 135 and 140 
mEq/L (mmol/L).  Titration guidelines are 
designed to achieve a change in serum 
sodium concentration of at least 4 to 
8 mEq/L (mmol/L)/24 hours but not 
exceeding 
.
3.2.4 Titration Guidelines and Rescue 
Therapy
Initiation and titration of tolvaptan must 
occur in a hospital setting.  Up titration can 
only take place on Treatment Day 2 (or 2a). 
Down titration can occur at any point in the 
trial but should be discussed with the 
medical monitor. Titration (up or down) 
may not occur within 20 hours of the 
previous dose. Up-titration is limited to no 
more than twice the previous dose.
The medical monitor should be contacted at 
any point if questions arise regarding 
titration or initiation of rescue therapy. The 
rationale for any up- or down-titration of 
tolvaptan must be documented.  The 
evaluation of serum sodium levels, 
management of tolvaptan titration and 
rescue therapy is described in Figure 3.2.4-
1.
3.2.4.1 Titration
Tolvaptan dose titration (after the initial 


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restriction) will be defined as rescue 
therapy.  The subject will be considered to 
have reached their clinical endpoint, and 
their data will be censored from that time 
forward.
Subjects receiving rescue therapy will be 
considered treatment failures.  A subject 
requiring rescue therapy at any time after 
enrollment will be discontinued from the 
trial treatment and will continue to Phase C 
to be followed as per protocol.
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 interruption, concomitant 
medication adjustment, fluid 
supplementation and/or withdrawal).

If serum sodium level increases by 
 
 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. 
3.2.4.2 Rescue Therapy
Subjects with worsening hyponatremia 
symptoms or whose serum sodium level 
declines may receive rescue therapy. 
….commercially available vaptans, or any 
treatment intended to raise the level of 
serum sodium at any time during the trial.
If at any point during the trial serum 
sodium levels or hyponatremia symptoms 
worsen or fail to improve adequately and 
definitive therapy (eg, isotonic or 
hypertonic saline) is required, the subject 
will be withdrawn from trial treatment to 
receive rescue therapy.  These subjects will 
continue to Follow-up Phase C for 
collection of safety information.  
Additional guidelines for rescue therapy 
concerning hyponatremia symptoms and 


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decreasing serum sodium level:

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.
Subjects who are randomized to the Early 
Withdrawal group will initially be observed 
to determine whether additional 
intervention is required to maintain 
appropriate serum sodium levels.  Those 
subjects whose serum sodium declines by 
4 mEq/L (mmol/L) or whose overall 
clinical condition requires further treatment 
to increase serum sodium will be treated 
per standard of care.  Any intervention 
intended to raise serum sodium level during 
the first 48 hours in the responder Early 
Withdrawal group (including fluid 
restriction) will be defined as rescue 
therapy.  These subjects will be considered 
to have reached their clinical endpoint, and 
their data will be censored from that time 
forward.
Subjects randomized to the Late 
Withdrawal group who receive rescue 
therapy will be considered treatment 
failures.  A subject requiring rescue therapy 
at any time after starting tolvaptan will be 
discontinued from trial treatment and will 
proceed to Follow-up Phase C.
3.2.4.3 Fluid Restriction Considerations
In subjects with chronic hyponatremia, 
fluid restriction coadministered with 
initiation of treatment with a vaptan has the 
potential to accentuate the rate of sodium 
correction and to cause overly rapid 
correction or over correction of 
hyponatremia.  Therefore, during treatment, 
subjects must have access to water and 
maintain fluid intake levels per institutional 
guidelines.  Fluid restriction at any time 


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during the trial including during the first 48 
hours after discontinuation of tolvaptan will 
be considered rescue therapy.
Old Text:  3.7 Trial Procedures
Figure 3.2.1-1 Titration Scheme 


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New Text: 3.7 Trial Procedures
Serum Sodium Decrease 
or
No  Change
Serum Sodium Increase
Assess 
Serum Sodium
↑ > 4 to ≤8 mEq/L/24h
and
≤140 mEq/L
↑> 8 mEq/L/24h
or
>140 mEq/L
↑≤4 mEq/L/24h
and
<135 mEq/L
Maintain dose
Interrupt dosing & 
Discuss with Medical Monitor
Titrate to next higher dose for 
body weight
Rescue therapy
= 
proceed to 
Follow-up Phase C
↑ ≥ 12 mEq/L/24h
or
>145 mEq/L
Interrupt dosing &
Call Medical Monitor 
Immediately
Worsening symptoms and/or Serum 
Sodium at or below baseline
Repeat STAT Serum 
Sodium, start rescue therapy
Asymptomatic and Serum Sodium ↓
≥4 mEq/L but above baseline
Consider rescue therapy
Asymptomatic and Serum Sodium ↓
≤ 3 mEq/L but above baseline
No action required.
Manage clinically
Figure 3.2.4-1 Titration and Rescue Therapy Scheme
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3.3 
Trial 
Populati
on
This trial will include up to 
100 male and female 
subjects aged 4 weeks (or 
44 weeks adjusted 
gestational age for premature 
births) to < 18 years, who 
have been diagnosed with 
euvolemic or hypervolemic 
hyponatremia 
(< 130 mmol/L) that persists 
despite initial standard 
background therapy 
(including fluid restriction 
and excluding a vasopressin 
antagonist).  It is expected 
that 70 subjects will have a 
serum sodium increase of 
4 mmol/L (ie, responders).
This trial will include up to 100 male and female subjects aged 
4 weeks (or 44 weeks adjusted gestational age) to < 18 years 
who have been diagnosed with euvolemic or hypervolemic 
hyponatremia (< 130 mEq/L [mmol/L]) that persists despite initial 
standard background therapy (including fluid restriction and 
excluding a vasopressin antagonist). Age groups will be enrolled 
such that 50% of these subjects will be < 10 years old and at least 
25% of subjects < 6 years old.  Subjects who are defined as 
responders will be further stratified by the magnitude of serum 
sodium response to tolvaptan (7 and > 7 mEq/L [mmol/L]), and 
underlying etiology of hyponatremia.
Subjects with euvolemic or hypervolemic hyponatremia eligible 
to be screened for participation in this trial include, but are not 
limited to, those diagnosed and admitted to a hospital for 
treatment of HF, hepatocellular disease (including cirrhosis), or 
SIADH/other.  ….


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The trial will be conducted 
at up to 50 centers globally.  
Subjects with euvolemic or 
hypervolemic hyponatremia 
eligible to be screened for 
participation in this trial 
include, but are not limited 
to, those diagnosed and 
admitted to a hospital for 
treatment of heart failure, 
hepatocellular disease 
(including cirrhosis), or 
SIADH…
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 
excluded from this trial (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).22  
Age groups will be stratified 
such that half (35) of these 
subjects will be age < 
10 years with at least 25% 
(17) of subjects < 6 years 
old.  Subjects who are 
defined as responders will be 
further stratified by the 
magnitude of serum sodium 
response to tolvaptan 
(7 and > 7 mmol/L) and 
underlying etiology of 
hyponatremia.
All subjects will be initially 
identified based on serum 
sodium concentrations that 
persist at levels 
All potential subjects must have chronic (48 hours) dilutional 
hyponatremia (euvolemic or hypervolemic) associated with HF, 
hepatocellular disease (including cirrhosis), or SIADH/other and 
be deemed by the investigator as likely to benefit from a therapy 
that raises serum sodium levels. The etiology of hyponatremia 
(presumed cause) must be documented and evaluated per 
Section 3.3.1.  Those subjects 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 are excluded from this trial. 
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 this protocol, persistent hyponatremia will be defined 
as serum sodium level < 130 mEq/L (mmol/L) documented as 
present for at least 48 hours.  Specifically, subjects must have 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 as 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 2-4 hours prior to the first dose of trial 
medication.
If a subject’s serum sodium level during the screening period is 
130 mEq/L (mmol/L), the subject will be determined to be a 
screen failure.  Subjects deemed screen failures may be 
rescreened, as appropriate.  Subjects who receive a randomization 
number may not be rescreened regardless of whether they receive 
trial medication.….
Hospitalized hyponatremic encephalopathy is seen in association 
with SIADH or in the immediate 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 
excluded from this trial (ie, hypoxia, infection, brain injury, 
neurosurgery, active seizure disorders, cerebritis, encephalopathy, 
central nervous system disorders such as cytotoxic and vasogenic 
cerebral edema, space-occupying brain lesion, or elevated AVP 
levels).22
3.3.1.1 General Guidelines
Investigators should assess subjects’ appropriateness to receive 
tolvaptan.  Investigators should ultimately use their medical 
judgment to make the final determination.  It remains the 
responsibility of the investigator to determine the etiology of 
hyponatremia and to assess the volume status for each subject 
using diagnostic tests (eg, fractional excretion of sodium [FENa], 
fractional excretion of urate [FE urate], urine osmolality, serum 
osmolality) employed in the usual clinical course of care.


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< 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 
Screening period is 130 
mmol/L, the subject will be 
determined a screen failure.  
Subjects deemed screen 
failures may be rescreened, 
as appropriate.  Subjects 
who receive a randomization 
number may not be 
rescreened regardless of 
whether they receive trial 
medication or complete the 
trial.
3.3.1 Tolvaptan 
Administration by 
Hyponatremia Etiology
Investigators should assess 
subjects’ appropriateness to 
receive tolvaptan.  Each 
investigator should 
ultimately use their medical 
judgment to make the final 
determination.  The 
guidelines listed in Table 
3.3.1-1 are to help guide the 
medical judgment of each 
investigator.
Table 3.3.1-1 Screening 
Algorithms by 
Hyponatremia Etiology
SIADH/
Other
CHF
Hepatoc
ellular 
Disease
Two 
serum 
sodium 
assessm
ents of < 
130 
mmol/L 
Two 
serum 
sodium 
assessm
ents of 
< 130 
mmol/L 
Two 
serum 
sodium 
assessme
nts of < 
130 
mmol/L 
3.3.1.2 Specific Guidelines by Etiology

Subjects diagnosed with hyponatremia secondary to SIADH 
will be evaluated specifically to ensure appropriate volume 
status.  Hypovolemic states are not compatible with tolvaptan 
administration.  Plasma and urine sodium, potassium, 
creatinine, and uric acid should be assessed in order to 
calculate and evaluate FENa and FE urate prior to dosing to 
ensure safety of tolvaptan administration.

For hyponatremia due to hepatocellular disease (including 
cirrhosis), in addition to the above guidelines, the underlying 
etiology of hepatocellular disease must be documented.  

For hyponatremia due to HF:  
6)
A definitive diagnosis of HF by a cardiologist must be 
documented.  
7)
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. 
The guidelines listed in Table 3.3.1-1 are to help guide the 
medical judgment of the investigator.
Table 3.3.1-1 Screening Algorithms by 
Hyponatremia Etiology
Etiology
Instruction
All 
etiologies
Two documented serum 
sodium assessments of < 130 
mEq/L (mmol/L) at least 12 
hours apart
One serum sodium assessment 
of < 130 mEq/L (mmol/L) 
within 2-4 hours prior to 
tolvaptan administration
Screen subjects for AKI criteria 
per exclusion criteria
Collect labsa
Calculate serum osmolality, 
FENa, and FE urate at 
pretreatment baseline only
HF
Cardiologist documented 
diagnosis of HF
Discontinue or stabilize diuretic 
use prior to tolvaptan 
administration
Hepato-
cellular 
disease 
(including 
cirrhosis)
The underlying etiology of 
hepatocellular disease must be 
documented


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at least 
12 hours 
apart
at least 
12 
hours 
apart
at least 
12 hours 
apart
One 
serum 
sodium 
assessm
ent 3 (
1) hours 
before 
tolvapta
n 
administ
ration of 
< 130 
mmol/L
One 
serum 
sodium 
assessm
ent 3 (
1) hours 
before 
tolvapta
n 
adminis
tration 
of < 130 
mmol/L
One 
serum 
sodium 
assessme
nt 3 (1) 
hours 
before 
tolvaptan 
administ
ration of 
< 130 
mmol/L
Screen 
subjects 
per AKI 
criteria 
per 
exclusio
n 
criteria
Screen 
subjects 
per AKI 
criteria 
per 
exclusio
n 
criteria
Screen 
subjects 
per AKI 
criteria 
per 
exclusio
n criteria
Collect 
labsa
Collect 
labsa
Collect 
labsa
Calculat
e plasma 
osmolali
ty, 
FENa, 
and FE 
urate at 
pretreat
ment 
baseline 
only
Calculat
e 
plasma 
osmolal
ity, 
FENa, 
and FE 
urate at 
pretreat
ment 
baseline 
only
Calculat
e plasma 
osmolalit
y, FENa, 
and FE 
urate at 
pretreat
ment 
baseline 
only
Cardiol
ogist 
docume
nted 
diagnosi
s of 
Disconti
nue or 
stabilize 
diuretic 
use 
prior to 
tolvapta
aRefer to Table 3.7.4.2-1 for complete lists of laboratory 
assessments.


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n 
adminis
tration 
aRefer to Table 3.7-1 and 
Table 3.7.4.2-1 for a 
complete list of 
laboratory 
assessments.
3.3.1.1 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 Screening period 
is 130 mmol/L, the subject 
will be determined a screen 
failure.  Subjects determined 
screen failures may be 
rescreened, as appropriate.  
Subjects who receive a 
randomization number may 
not be rescreened regardless 
of whether they receive trial 
medication or complete the 
trial.  At Screening/Baseline, 
urine chemistry should be 
assessed and the plasma 
osmolality, FENa, and FE 
urate should be calculated 
for all subjects prior to the 
first dose of tolvaptan.  
Please see Table 3.7-1 for a 
full schedule of assessments 
and timing.
Subjects must be screened 
per the AKI criteria detailed 
in the exclusion criteria 
(Section 3.4.3).


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
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 Screening period 
is 130 mmol/L, the subject 
will be determined a screen 
failure.  Subjects determined 
screen failures may be 
rescreened, as appropriate.  
Subjects who receive a 
randomization number may 
not be rescreened regardless 
of whether they receive trial 
medication or complete the 
trial.  At Screening/Baseline, 
urine chemistry should be 
assessed and the plasma 
osmolality, FENa, and FE 
urate should be calculated 
for all subjects prior to the 
first dose of tolvaptan.  
Please see Table 3.7-1 for a 
full schedule of assessments 
and timing.
5)
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 


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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 exclusion criteria 
(Section 3.4.3).
3.3.1.2 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 Screening period 
is 130 mmol/L, the subject 
will be determined a screen 
failure.  Subjects determined 
screen failures may be 
rescreened, as appropriate.  
Subjects who receive a 
randomization number may 
not be rescreened regardless 
of whether they receive trial 
medication or complete the 
trial.  At Screening/Baseline, 
urine chemistry should be 
assessed and the plasma 
osmolality, FENa, and FE 
urate should be calculated 
for all subjects prior to the 
first dose of tolvaptan.  
Please see Table 3.7-1 for a 
full schedule of assessments 
and timing.
Subjects must be screened 
per the AKI criteria detailed 
in the exclusion criteria 
(Section 3.4.3).
The underlying etiology of 
hepatocellular disease must 


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be documented.
3.4 
Eligibili
ty 
Criteria
Eligible subjects must satisfy all informed consent requirements, 
as well as meet all inclusion and exclusion criteria.  Subjects who 
do not meet all of these requirements are to be defined as screen 
failures and may rescreen, if eligible, at a later date.
3.4.2 
Inclusio
n 
Criteria
Eligible subjects must satisfy 
all informed consent 
requirements, as well as 
meet all inclusion criteria 
and none of the exclusion 
criteria.  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 to be 
defined as screen failures 
and may rescreen if eligible 
at a later date….
3.5 
Outcom
e 
Variabl
es
3.5.1 Primary Outcome 
Variables
3.5.2
Efficacy Variables
For subjects with serum 
sodium increases of 
4mmol/L (ie, responders), 
the primary endpoint is the 
change in serum sodium 
concentration from 
randomization (at the end of 
Day 2/3 [end of Phase A]) to 
the end of Day 4/5 (Phase B) 
for Early compared to Late 
Withdrawal groups.
3.5.3 Secondary Outcome 
Variables
3.5.4 Efficacy Variables
For all subjects, the key 
secondary endpoint is the 
change in serum sodium 
concentration at the end of 
3.5.1 Primary Efficacy Outcome Variable
For subjects with serum sodium level increases of 4 mEq/L 
(mmol/L) (ie, responders), change in serum sodium concentration 
from Day 2 (or 2a) at the end of Treatment Phase A to the end of 
Treatment Phase B for Early compared to Late Withdrawal 
groups.
3.5.2 Key Secondary Efficacy Outcome Variable
For all subjects, the key secondary endpoint is the change in 
serum sodium concentration at the end of Day 2 (or 2a) in 
Treatment Phase A from baseline.
3.5.3.1 Safety Variables

Percentage of subjects with overly rapid increase in serum 
sodium level (
 
)

Change in serum sodium level from 24 hours post-last dose to 
7 days post-last dose

Percentage of subjects requiring rescue therapy (other than 
fluid restriction) during Treatment Phase A and Treatment 
Phase B 

Percentage of subjects requiring fluid restriction during 


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Day 2/3 from baseline in 
Phase A.
3.5.4.1 Safety Variables

Percentage of subjects 
with overly rapid 
increase in serum 
sodium (12mmol/L in 
24 hours after first 
dose).

Percentage of subjects 
requiring rescue 
medication during Phase 
A and Phase B of the 
trial.

Change in serum 
sodium from 24 hours 
post-last dose to 14 days 
post-randomization.

Vital signs, blood 
pressure, clinical 
laboratory tests, and 
body weight.
3.5.4.3 Pharmacodynamic 
Variables
Pharmacodynamic endpoints 
are fluid intake, urine output, 
and fluid balance 
(intake −output) every 
6 hours on Days 1 and 2 
(Phase A).
3.5.5 Exploratory 
Variables
3.5.5.1 Efficacy Variables

The other efficacy 
endpoint in 
nonresponders 
continuing on tolvaptan 
therapy is the change in 
trough serum sodium 
concentration on Day 6 
compared to Day 4.
3.5.5.2 Safety Variable
The other safety variable is 
neurological examinations.
3.5.5.3 Pharmacodynamic 
Variables
The other PD endpoints 
include:
Treatment Phase A and Treatment Phase B 

Vital signs, blood pressure, clinical laboratory tests, body 
weight, and neurological examinations
3.5.3.3 Pharmacodynamic Variables
Pharmacodynamic endpoints are fluid intake, urine output, and 
fluid balance (intake minus output) every 6 hours on Days 1 and 2 
in Treatment Phase A.
3.5.4 Exploratory Variables

Efficacy will be assessed in nonresponders continuing on 
tolvaptan therapy by change from baseline in serum sodium 
concentration at the end of Treatment Phase B compared to 
the end of Treatment Phase A

In all subjects, 24-hour excretion of sodium, creatinine, and 
urine osmolality on Days 1 and 2

24-hour sodium clearance on Day 1

Neurocognition test battery

QoL assessments


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In all subjects, 24-hour 
excretion of sodium, 
creatinine, and osmoles 
on Days 1 and 2.
3.6 
Measur
es to 
Minimiz
e/void 
Bias
This is an open-label trial.  
Subjects defined as 
responders (serum sodium 
increase of 4 mmol/L) will 
be randomized to either the 
Early Withdrawal group or 
the Late Withdrawal group.  
The assignments will be 
stratified by age (< 10 and 
10 to < 18 years), magnitude 
of serum sodium response (
7 and > 7 mmol/L), and 
underlying etiology of 
hyponatremia.  The dose of 
the investigational medicinal 
product (IMP) assigned to a 
subject is determined by the 
subject’s age, weight, and 
the use of CYP3A4 
inhibitors.
This is an open-label trial.  Subjects defined as responders from 
Treatment Phase A will be randomized to either the Early 
Withdrawal group or the Late Withdrawal group in Treatment 
Phase B.  Treatment assignments for Treatment Phase B will be 
based on a computer-generated randomization code provided by 
OPDC Biometrics Department.
3.7 
Trial 
Procedu
res
Treatment in this trial will be 
up to 5 days.  Any initiation 
or titration of tolvaptan must 
occur in a hospital setting.  
Parents or legal guardians 
will consent and subjects 
will assent (as appropriate) 
and be screened up to 
24 hours prior to dosing.  
Subjects who meet the 
inclusion and exclusion 
criteria will be enrolled and 
will be administered a 3.75-, 
7.5-, or 15-mg dose based on 
age, weight, and the use of 
CYP3A4 inhibitors.  
At the end of Treatment Day 
2 (optionally Day 3 [Phase 
A]), subjects who are 
responders will be 
randomized to either 
continue treatment with 
tolvaptan for 2 additional 
days (Late Withdrawal) or to 
discontinue tolvaptan 
treatment (Early 
Withdrawal).  Subjects who 
Treatment in this trial will last up to 5 days.  Any initiation or 
titration of tolvaptan must occur in a hospital setting.  Parents or 
legal guardians must provide informed consent and subjects must 
provide informed assent (as appropriate) and be screened up to 
24 hours prior to dosing.  
In Treatment Phase A, subjects who meet the inclusion and 
exclusion criteria will be enrolled and will be administered a 
3.75-, 7.5-, or 15-mg dose tablet based on age, weight, and the use 
of CYP3A4 inhibitors.  At the end of Day 2 (or 2a) in Treatment 
Phase A, subjects who are responders will be randomized to either 
continue treatment with tolvaptan for 2 additional days (Late 
Withdrawal) or to discontinue tolvaptan treatment (Early 
Withdrawal).
In Treatment Phase B, subjects who are nonresponders may 
continue on tolvaptan therapy for 2 additional days or may be 
withdrawn from tolvaptan to be treated per the investigator’s 
preferred standard of care.  During Treatment Phase B, subjects in 
the Late Withdrawal group and nonresponders continuing 
treatment will continue to receive tolvaptan for 2 additional days 
and all subjects will have serum sodium levels measured at 12 (
4) hours post-dose and at trough each day.  Subjects in the Early 
Withdrawal group should be monitored for the first 48 hours post-
last dose.
In Follow-up Phase C, all subjects will be monitored and will 
have an additional serum sodium measurement at 72 (4) hours 


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are nonresponders may 
continue on tolvaptan 
therapy for 2 additional days 
at their highest dose or may 
be withdrawn from tolvaptan 
to be treated per the 
investigator’s preferred 
standard of care.  
During Phase B, subjects in 
the Late Withdrawal group 
and nonresponders 
continuing treatment will 
continue treatment with 
tolvaptan for 2 additional 
days and all subjects will 
have serum sodium 
measured every 12 (4) 
hours post-randomization. 
In Phase C, or Follow-up 
Phase, subjects will be 
monitored and treated as 
clinically warranted per the 
investigator’s preferred 
standard of care for up to 
3 additional days after the 
last dose of tolvaptan (note:  
the Early Withdrawal group 
should be monitored for the 
first 48 hours post-last dose) 
and will have an additional 
serum sodium concentration 
measurement at 72 (4) 
hours post-randomization 
and 7 (1) days post-
randomization.  A final 
safety follow-up telephone 
contact/visit will be 
performed 14 (+ 2) days 
post-randomization.
Trial assessment time points 
are summarized in Table 
3.7-1.
Pharmacokinetic samples 
will be obtained on Day 1 
(Phase A) for all subjects 
and at 24 and 48 hours post-
randomization for tolvaptan-
treated subjects in Phase B, 
including subjects who are 
post-last dose as well as at 7 (1) days post-last dose.  A final 
safety follow-up telephone contact/visit will be performed 
14 (+ 2) days post-last dose.
Trial assessment time points are summarized in Table 3.7-1.  
Section 3.7.1 provides a flow overview that describes the 
sequence of assessments during a visit. Section 3.7.2 provides 
details around efficacy assessments, Section 3.7.3 provides details 
around pharmacokinetic/pharmacodynamic assessments and 
Section 3.7.4 provides details around safety assessments.
Pharmacokinetic samples will be obtained for all subjects on Day 
1 at 2 and 8 hours post-first dose and at trough on Days 2, 3, 4 and 
5 for all subjects when dosed with tolvatpan on Days 1, 2, 3, and 
4, respectively, regardless of responder status.  Once adequate PK 
data are obtained, PK sampling will be discontinued for all 
subjects.
Subjects will be required to be in a hospital setting during 
initiation or titration of tolvaptan.  A subject is allowed to be 
discharged, if they:
1) Continue to come to the clinic for daily study assessments and
2) Are either: 
a) A nonresponder on standard of care or 
b) On a stable dose of study drug, or 
c) In the early withdrawal group without study treatment.  
Follow-up for all subjects 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.


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deemed nonresponders and 
continue on tolvaptan.  Once 
adequate PK data are 
obtained, PK sampling will 
be discontinued for all 
subjects.


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3.7 Trial Procedures
Table 3.7-1 Schedule of Assessments
Procedures
Phase A
Phase B
Phase C
Screening/
Baseline Visit 
Days −2 to −1
Initial Treatment Phase
Days 1 and 2/3
Randomization 
Phase
Days 3/4 and 4/5
Follow-up 
Phase
Day 5/6 or ET
Follow-up 
(7 [1] days 
post-random.)
Follow-up 
Phone Call/Visit 
(14 [+ 2] days 
post-random.)
Informed consent and assent
X
Review inclusion/exclusion
  criteria
X
Day 1:  predose
Demographic information
X
Medical and hyponatremia
  history
X
Alcohol and drug screen
X
Pregnancy test (if applicable)a
X
Serum chemistry
X
X
Plasma osmolality, FeNa, and 
  Fe urate
X
TSH and cortisolb
X
Hematology and coagulation
X
X
Urinalysis
X
X
Urine chemistry
X
Days 1 and 2 only:  6-hour 
intervals starting at Hour 0
Serum sodiumc
2 assessments at 
least 12 hours 
apart
Baseline (Hour 0; within 
3 1 hours of dosing), 
12 hours post-first dose, and 
24 (4) hours post-previous 
dose
12, 24, 36, and 
48 (4) hours 
post-random.
72 (4) hours 
post-random.
X
Vital signsd
X
2, 4, 8, and 24 hours 
post-first dose and on Day 3, 
if applicable
X
X
X
Fluid intake and urine volume
Days 1 and 2 only:  6-hour 


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Table 3.7-1 Schedule of Assessments
Procedures
Phase A
Phase B
Phase C
Screening/
Baseline Visit 
Days −2 to −1
Initial Treatment Phase
Days 1 and 2/3
Randomization 
Phase
Days 3/4 and 4/5
Follow-up 
Phase
Day 5/6 or ET
Follow-up 
(7 [1] days 
post-random.)
Follow-up 
Phone Call/Visit 
(14 [+ 2] days 
post-random.)
intervals starting at Hour 0
PK plasma samplese
1, 2, 4, 12, and 24 hours 
post-first dose
24 and 48 hours 
post-random.
ET only
12-lead ECG
X
Directed physical examination
X
Baseline (Hour 0), 8 hours 
post-first dose, and Day 2/3
Daily
X
X
Neurological examination
X
Baseline (Hour 0), 8 hours 
post-first dose, and Day 2/3
Daily
X
X
Body height and weightf
X
Daily (predose):  weight only
Daily (predose):  
weight only
Weight only
Weight only
Clinical assessmentg
X
End of Day 2/3
Day 4/5
X
X
Randomization
Responders:  End of Day 2 
(optionally Day 3)
Tolvaptan dosingh
Once daily
Once dailyi
Follow-up phone call
X
Concomitant medications
<------------------------------------------------------------------------------------------------------------------------------------------------>
Adverse events
<------------------------------------------------------------------------------------------------------------------------------------------------>
ECG = electrocardiogram; ET = early termination; post-random. = post-randomization; TSH = thyroid-stimulating hormone.
Note:  See Table 3.7.4.2-1 for further details regarding laboratory tests.
aPregnancy tests will be performed on female subjects 12 years of age and all female subjects < 12 years of age if menstruation has started.
bResults of these tests will further characterize hyponatremia etiology for the Hyponatremia History CRF and are not required to determine eligibility.
cResults of the serum sodium from the chemistry panel are sufficient for the protocol.  It is not necessary to collect a separate serum sodium concentration.
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.
eAn ET sample will be collected only if ET is before the last scheduled PK assessment.  The PK samples in Phase B will be collected for all subjects who are 
on tolvaptan, including subjects who are deemed nonresponders and continue on tolvaptan.  Pharmacokinetic blood samples should be taken within 
5 minutes for each draw up to 2 hours postdose and 30 minutes for later time points.


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fWeight will be taken predose as possible during administration of tolvaptan.
gSubject clinical status assessments will be performed per inpatient standard of care, ie, review patient chart entries (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], any examination findings, medical problem list changes, and fluid intake and output) to evaluate 
overall subject eligibility in terms of hyponatremia state.
hThe dose will be titrated at a minimum of 24 (4)-hour intervals 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.  Each upward titration may not exceed twice the previous dose.  

iIn Phase B, tolvaptan will only be administered to subjects randomized to the Late Withdrawal group and to nonresponders who are continuing on 
tolvaptan.  Subjects randomized to the Late Withdrawal group will receive the same dose that they received on Day 2/3; nonresponders may 
continue on tolvaptan therapy for 2 additional days at their highest dose at the discretion of the investigator.


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3.7 Trial Procedures
Table 3.7-1 Schedule of Assessments
Procedures
Screening
Treatment Phase A
Treatment Phase B
Follow-up Phase C
Day -2 
and -1
Day 1
Day 2
Day 2a 
(optional)
Day 3
Day 4
Day 5
72 (4) h 
post last 
dose
7 (1) 
days post-
last dose
14 (+2) 
days post-
last dose
Early 
Termin-
ation (ET)
Informed Consent/Assent
X
Inclusion/exclusion 
criteriaa
X
X
Demographic information
X
Medical and 
hyponatremia history
X
Vital signsb
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
Height
X
Body weightc
X
X
X
X
X
X
X
X
X
X
Directed physical 
examination
X
X
X
X
X
X
X
X
X
Tanner staging
X
Neurological examination
X
X
X
X
X
X
X
X
Neurocognitive 
assessmentd
X
X
X
X
X
X
X
X
X
X
Quality of life assessment
X
X
X
Clinical status assessmente
X
X
X
X
X
X
X
X
X
Alcohol/drug screen
X
Pregnancy test (if 
applicable)f
X
Fluid intakeg
X
X
Urine volumeg
X
X
Urinalysis
X
X
X
Urine chemistryg,h
X
X
X
Serum sodiumi
X
X
X
X
X
X
X
X
X
X


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Table 3.7-1 Schedule of Assessments
Procedures
Screening
Treatment Phase A
Treatment Phase B
Follow-up Phase C
Day -2 
and -1
Day 1
Day 2
Day 2a 
(optional)
Day 3
Day 4
Day 5
72 (4) h 
post last 
dose
7 (1) 
days post-
last dose
14 (+2) 
days post-
last dose
Early 
Termin-
ation (ET)
Hematology, coagulation, 
and serum chemistryj
X
X
X
Serum osmolality, FENa, 
and FE urate
X
TSH and cortisolk
X
PK plasma samplesl
X
X
X
X
X
X
Tolvaptan dosingm
X
X
X
X
X
Assessment for response 
to tolvaptan
X
X
Palatability assessment
X
Randomization
X
Follow-up phone call or 
visit
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; TSH = thyroid-stimulating hormone.
aInclusion/exclusion criteria will be checked at screening and predose on Day 1.
bVital signs to be assessed include supine blood pressure, heart rate, respiratory rate, and temperature.  Vital signs should be assessed prior to any blood 
draws.
cWeight will be taken predose as possible.
dNeurocognitive assessments are closely tied to serum sodium assessments and should be done within 1 hour of sodium blood draws.
eClinical status assessments will be performed per inpatient standard of care, ie, review patient chart entries (including hyponatremia assessment notes and
laboratory results [trial and nontrial specific], any examination findings, medical problem list changes, and fluid intake and output) to evaluate overall 
subject eligibility in terms of hyponatremia state.
fUrine pregnancy tests will be performed on female subjects 12 years of age and all female subjects < 12 years of age if menstruation has started.
gIntervals starting immediately after dosing at Hour 0 (0-6, 6-12, 12-18, and 18-24 hours).
hSamples within a collection interval are to be refrigerated and pooled. An aliquot for urine chemistry tests will be taken for each collection interval. Uric acid 
is to be measured at screening only.
iSerum sodium assessments are closely tied to neurocognitive assessments, dosing time points and PK blood draws.

Screening: 2 assessments should be taken, at least 12 hours apart (may be part of medical history). 1 assessment can be combined with the serum 
chemistry panel.


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
Treatment Phase A: Baseline [STAT] assessment will be at 2-4 hours prior to first dose. Post-first dose assessments: 8 and 24 (trough) hours. Then 
every 12 hours thereafter (alternating 12 hours post-dose and at trough)

Treatment Phase B: Assessments to be taken every 12 hours (alternating 12 hours post-dose and at trough) 

Treatment Phase C: Assessments to be taken at 72 (± 4) hours post-last dose (can be combined with the serum chemistry panel) and at the 7 day 
post-last dose visit.
jSerum chemisty panel includes serum sodium and assessments can be combined for visits where both assessments are indicated.
kResults of these tests will further characterize hyponatremia etiology for the Hyponatremia History CRF and are not required to determine eligibility.  
Subjects who have clinically relevant TSH or cortisol levels may not respond properly to tolvaptan and will be withdrawn from the trial.
lPK samples are closely tied to dosing time points and serum sodium assessments. An ET sample will be collected only if ET is before the last scheduled PK 
assessment.

In Treatment Phase A PK samples should be collected at 2 and 8 hours and at trough post-first dose.

In Treatment Phase B PK will be assessed in subjects continuing treatment with tolvaptan (Late Withdrawal group and nonresponders continuing on 
tolvaptan) at trough on Days 3, 4 and 5.
mThe tolvaptan dose will be titrated based on serum sodium levels as described in Section 3.2.4.


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3.7.1 Schedule 
of Assessments
3.7.1.1 Phase A:  Treatment Phase
3.7.1.2 Screening/Baseline
The following procedures will be 
performed during the Screening/Baseline 
Visit (Days −2 to −1 prior to dosing) 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.
a)
Informed consent will be 
obtained from each subject’s 
parent or legal guardian prior 
to any trial procedures being 
conducted.
b)
Each subject who is able will 
indicate willingness to 
participate in the trial by 
signing or marking an assent 
form (as applicable) supplied 
for this purpose.
2)
Inclusion and exclusion criteria 
will be reviewed.
3)
Demographic information will be 
collected.
a)
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.  
b)
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.
c)
Any observable symptoms of 
hyponatremia will be assessed 
and recorded separately.
4)
Alcohol and drug screens will be 
performed.
5)
A urine or serum pregnancy test 
will be performed on all female 
subjects 12 years of age and all 
female subjects < 12 years of age 
if menstruation has started.
6)
Two samples for serum sodium 
3.7.1.1 Screening
The procedures listed below will be 
performed during the Screening Visit 
(Days −2 to −1) to ensure that 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.
a)
Informed consent will be 
obtained from each subject’s 
parent or legal guardian prior 
to any trial procedures being 
conducted.
b)
Each subject who is able will 
indicate willingness to 
participate in the trial by 
signing or marking an assent 
form (as applicable) supplied 
for this purpose.
2)
Inclusion and exclusion criteria 
will be reviewed.
3)
Demographic information will be 
collected.
4)
Medical and hyponatremia history 
will be recorded.  
a)
Medical history should 
include the subject’s current 
list of medical problems that 
impacts the subject’s current 
hospital stay.  
b)
The hyponatremia medical 
history should include the 
etiology of subject’s 
hyponatremia (see 
Section 3.2.1) and what 
treatment was administered 
prior to trial enrollment.  A 
detailed history specific to 
etiology of hyponatremia will 
also be recorded.
c)
Any observable symptoms of 
hyponatremia will be assessed 
and recorded.
5)
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.
6)
A resting 12-lead 
electrocardiogram (ECG) will be 
performed after the subject has 


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testing will be collected at least 12 
hours apart.  (These blood draws 
can be combined with the serum 
chemistry panel as appropriate to 
minimize blood draws.)
7)
Urinalysis and urine chemistry 
laboratory samples will be 
collected.
8)
Plasma osmolality, FENa, and FE 
urate will be calculated.
9)
Thyroid-stimulating hormone 
(TSH) and cortisol blood samples 
will be collected to determine need 
for alternate mode of therapy.
10) 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 the blood 
draws.
11) A resting 12-lead 
electrocardiogram (ECG) will be 
performed after the subject has 
been supine and at rest 10 
minutes.
12) A directed physical examination 
will be performed.
13) A neurological examination will 
be performed.
14) Body height and weight will be 
measured and body mass index 
will be calculated.
15) Clinical status assessments will be 
performed per inpatient standard 
of care, ie, patient chart entries 
will be reviewed (including 
hyponatremia assessment notes, 
including laboratory results [trial 
and nontrial specific], any 
examination findings, medical 
problem list changes, and fluid 
intake and output) to evaluate 
overall subject eligibility in terms 
of hyponatremia state.
16) Concomitant medications will be 
recorded.
17) Adverse events will be assessed.
3.7.1.2.1 Day 1
The following procedures will be 
performed on Day 1 for all subjects:
1)
Inclusion and exclusion criteria 
will be reviewed prior to dosing to 
confirm eligibility.
been supine and at rest 10 
minutes.
7)
Body height and weight will be 
measured.
8)
A directed physical examination 
will be performed.
9)
Tanner staging will be performed. 
10) A neurological examination will 
be performed.
11) A neurocognitive assessment will 
be performed, as appropriate by 
age and where available.
12) Quality-of-life (QoL) assessment 
will be performed, as appropriate 
by age and where available.
13) Clinical status assessments will be 
performed per inpatient standard 
of care.
14) Alcohol and drug screens will be 
performed, as age appropriate.
15) A urine pregnancy test will be 
performed on all female subjects 
12 years of age and all female 
subjects < 12 years of age if 
menstruation has started. 
16) Urinalysis and urine chemistry 
laboratory samples will be 
collected for analysis. 
17) Two blood samples for serum 
sodium testing will be collected at 
least 12 hours apart and can be 
part of the recent medical history 
to document chronic 
hyponatremia.  (One of these 
blood draws can be combined 
with the serum chemistry panel as 
appropriate to minimize blood 
draws.)
18) Hematology, coagulation, and 
serum chemistry laboratory 
samples will be collected for 
analysis.
19) Serum osmolality, FENa, and FE 
urate will be determined.
20) Thyroid-stimulating hormone 
(TSH) and cortisol blood samples 
will be collected to determine 
possible need for alternate mode 
of therapy.
21) Concomitant medications will be 
recorded.
22) Adverse events will be recorded.
3.7.1.2 Treatment Phase A
During Treatment Phase A every effort 


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2)
Blood samples for STAT serum 
sodium testing will be collected at 
baseline (Hour 0; within 3 [
1] hours prior to dosing) and 12 
hours post-first dose per protocol, 
but can be assessed as often as 
desired per clinician preference.
3)
Vital signs will be assessed at 2, 4, 
and 8 hours post-first dose.  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 the 
blood draws at each nominal time 
point.
4)
Fluid intake and urine volume will 
be recorded at 6-hour intervals 
starting at Hour 0.
5)
Urine chemistry will be assessed 
using 6-hour collection intervals 
starting at Hour 0.
6)
Any observable symptoms of 
hyponatremia will be assessed at 
baseline (prior to dosing) to 
confirm eligibility.
7)
A directed physical examination 
will be performed at baseline 
(prior to dosing) and 8 hours post-
first dose.
8)
A neurological examination will 
be performed at baseline (prior to 
dosing) and 8 hours post-first dose.
9)
Body weight will be measured 
predose as possible.
10) Blood samples for PK analysis of 
tolvaptan will be collected at 1, 2, 
4, and 12 hours post-first dose.
11) Tolvaptan will be administered as 
a 3.75-, 7.5-, or 15-mg dose based 
on weight and the use of CYP3A4 
inhibitors.
12) Concomitant medications will be 
recorded.
13) Adverse events will be assessed.
3.7.1.2.2 Day 2 (Including Day 3, if 
Appropriate)
The following procedures will be 
performed on Day 2/3 for all subjects:
1)
A blood sample for STAT serum 
sodium testing should be taken at 
24 (4) hours post-previous dose 
and the results known prior to 
should be made to have accurate dosing 
time points and follow the sequence of 
assessments specified below as PK/PD 
assessments, serum sodium blood draws 
and neurocognitive assessments are closely 
tied to dosing time points.
3.7.1.2.1 Day 1
The procedures listed below will be 
performed on Day 1 for all subjects.  
Predose
1)
Any observable symptoms of 
hyponatremia will be assessed 
within 2 hours prior to first dose 
to confirm eligibility as part of a 
clinical status assessment.
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 
assessed prior to blood draws.
3)
A blood sample for STAT serum 
sodium testing will be collected 
within 2 to 4 hours prior to dosing. 
4)
A neurocognitive assessment will 
be performed, as appropriate by 
age and where available.
5)
Body weight will be measured.
6)
A directed physical examination 
will be performed.
7)
A neurological examination will 
be performed.
8)
Inclusion and exclusion criteria 
will be reviewed and confirmed
Dosing
9)
Tolvaptan will be administered.
Postdose
10) A blood sample will be collected 
at 2 hours post-first dose for PK 
analysis
11) Vital signs will be assessed at 4 
and 8 hours post-first dose.  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 at 8 hours.
12) Fluid intake will be recorded at 6-
hour intervals starting at Hour 0 
(0-6, 6-12, 12-18, and 18-24 
hours).
13) Urine will be collected at 6-hour 
intervals starting at Hour 0 (0-6, 


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subsequent tolvaptan dosing.
2)
Vital signs will be assessed at 24 
hours post-first dose and on Day 3, 
if applicable.  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 the blood 
draws.
3)
Fluid intake and urine volume will 
be recorded at 6-hour intervals on 
Day 2.
4)
Urine chemistry will be assessed 
using 6-hour collection intervals 
on Day 2.
5)
A directed physical examination 
will be performed.
6)
A neurological examination will 
be performed.
c)
Body weight will be measured 
predose daily during 
administration of tolvaptan as 
possible.
d)
A blood sample for PK 
analysis of tolvaptan will be 
collected at 24 hours post-first 
dose.
7)
If the subject’s serum sodium 
concentration is < 135 mmol/L and 
a 4-mmol/L increase, tolvaptan 
should be titrated per the titration 
guidelines (Section 3.2.1) for the 
assigned weight group.
8)
Clinical status assessments will be 
performed at the end of Day 2/3 
per inpatient standard of care, ie, 
patient chart entries will be 
reviewed (including hyponatremia 
assessment notes, including 
laboratory results [trial and 
nontrial specific], any examination 
findings, medical problem list 
changes, and fluid intake and 
output) to evaluate overall subject 
eligibility in terms of 
hyponatremia state.
2)
Concomitant medications will be 
recorded.
3)
Adverse events will be assessed.
a)
At the end of Day 2 
(optionally Day 3), subjects 
who are responders (serum 
sodium increase of 4 
6-12, 12-18, and 18-24 hours). 
Subjects should be asked to void 
just prior to the end time of each 
collection interval, as possible. 
a)
Urine volume will be 
determined from urine voids 
made during the 6-hour 
collection intervals which will 
be pooled prior to 
determination of final 
volume.
b)
A urine chemistry sample will 
be collected and assessed 
from each 6-hour volume 
interval starting at Hour 0 (0-
6, 6-12, 12-18, and 18-24 
hours).
14) Blood samples will be collected 
concurrently at 8 hours post-first 
dose for:
a)
Serum sodium testing 
b)
PK analysis
15) A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
16) A neurological examination will 
be performed at 8 hours post-first 
dose.
Throughout the visit
17) Concomitant medications will be 
recorded.
18) Adverse events will be assessed.
3.7.1.2.2 Day 2
The following procedures will be 
performed on Day 2 for all subjects.  
Trough (24 hours post-first dose)
At trough the following assessments will be 
performed:
1)
Vital signs will be assessed.  
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 blood draws.
2)
Blood samples will be collected 
concurrently at 24 (4) hours for:
a)
A blood sample for STAT 
serum sodium testing should 
be taken and the results 
known prior to subsequent 
tolvaptan dosing. 
b)
A blood sample for PK 
analysis of tolvaptan (at a 


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mmol/L) will be randomized 
to the Early or Late 
Withdrawal group.
11) Subjects who are nonresponders at 
the end of Day 3 may continue on 
tolvaptan therapy for 2 additional 
days at their highest dose or may 
be withdrawn from tolvaptan to be 
treated per the investigator’s 
preferred standard of care.
3.7.1.3 Phase B:  Randomization Phase
The following procedures will be 
performed on Days 3/4 and 4/5 for all 
subjects:
1)
A blood sample for STAT serum 
sodium testing should be taken 12, 
24, 36, and 48 (4) hours post-
randomization and the results 
known prior to subsequent 
treatment.
2)
Vital signs (blood pressure, heart 
rate, respiratory rate, and 
temperature) will be assessed daily 
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 daily.
4)
A neurological examination will 
be performed daily.
5)
Body weight will be measured 
predose daily during 
administration of tolvaptan as 
possible.
6)
Blood samples for PK analysis of 
tolvaptan will be collected at 24 
and 48 hours post-randomization 
for all subjects on tolvaptan, 
including subjects who are deemed 
nonresponders and continue on 
tolvaptan.
7)
Tolvaptan will be administered 
once daily to subjects randomized 
to the Late Withdrawal group and 
nonresponders continuing on 
tolvaptan.
8)
Subjects randomized to the Early 
Withdrawal group will be initially 
observed to determine whether 
additional intervention is required 
to maintain appropriate serum 
sodium levels.  Nonresponders 
discontinuing tolvaptan will be 
central lab) will be collected 
at 24 hours post-first dose.
3)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
Predose
4)
Complete fluid intake and urine 
volume collection for specified 
intervals prior to next dosing with 
tolvaptan.
5)
Fluid intake will be recorded at 6-
hour intervals starting at Hour 0 
(0-6, 6-12, 12-18, and 18-24 
hours).
6)
Urine will be collected at 6-hour 
intervals starting at Hour 0 (0-6, 
6-12, 12-18, and 18-24 hours). 
Subjects should be asked to void 
just prior to the end time of each 
collection interval, as possible. 
a)
Urine volume will be 
determined from urine voids 
made during the 6-hour 
collection intervals which will 
be pooled prior to 
determination of final 
volume.
b)
A urine chemistry sample will 
be collected and assessed 
from each 6-hour volume 
interval starting at Hour 0 (0-
6, 6-12, 12-18, and 18-24 
hours).
7)
A directed physical examination 
will be performed.
8)
Body weight will be measured.
9)
A neurological examination will 
be performed.
Dosing
10) Tolvaptan will be administered. 
If the subject’s serum sodium 
concentration is < 135 mEq/L 
(mmol/L) and a 4 mEq/L 
(mmol/L) increase, tolvaptan dose 
should be adjusted per the titration 
guidelines (Section 3.2.4) for the 
assigned weight group.
Postdose
2)
Assess palatability of tolvaptan 
tablets for subjects.
3)
Fluid intake will be recorded at 6-
hour intervals starting at Hour 0 
(0-6, 6-12, 12-18, and 18-24 
hours).
4)
Urine will be collected at 6-hour 


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treated per the investigator’s 
preferred standard of care for 
3 additional days after the last dose 
of tolvaptan.
9)
Clinical status assessments will be 
performed on Day 4/5 per 
inpatient standard of care, ie, 
patient chart entries will be 
reviewed (including hyponatremia 
assessment notes, including 
laboratory results [trial and 
nontrial specific], any examination 
findings, medical problem list 
changes, and fluid intake and 
output) to evaluate overall subject 
eligibility in terms of 
hyponatremia state.
10) Concomitant medications will be 
recorded.
11) Adverse events will be assessed.
3.7.1.4 Phase C:  Follow-up Phase
3.7.1.4.1 Follow-up (Day 5/6)/Early 
Termination
The following procedures will be 
performed on Day 5/6 or at early 
termination (ET) for all subjects:
1)
Hematology, coagulation, and 
serum chemistry laboratory 
samples will be collected.
2)
A blood sample for serum sodium 
testing will be collected at 72 
(4) hours post-randomization.  
(This blood draw can be combined
with the chemistry panel as 
appropriate to minimize blood 
draws.)
3)
A urinalysis laboratory sample will 
be collected.
4)
A blood sample for PK analysis of 
tolvaptan will be collected at ET 
only if ET occurs before the last 
scheduled PK assessment (ie, 48 
hours post-randomization for 
subjects continuing on tolvaptan).
5)
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 the blood 
draws.
6)
A directed physical examination 
will be performed.
7)
A neurological examination will 
intervals starting at Hour 0 (0-6, 
6-12, 12-18, and 18-24 hours). 
Subjects should be asked to void 
just prior to the end time of each 
collection interval, as possible. 
a)
Urine volume will be 
determined from urine voids 
made during the 6-hour 
collection intervals which will 
be pooled prior to 
determination of final 
volume.
b)
A urine chemistry sample will 
be collected and assessed 
from each 6-hour volume 
interval starting at Hour 0 (0-
6, 6-12, 12-18, and 18-24 
hours).
5)
Clinical status assessments will be 
performed per inpatient standard 
of care, ie, patient chart entries 
will be reviewed (including 
hyponatremia assessment notes, 
including laboratory results [trial 
and nontrial specific], any 
examination findings, medical 
problem list changes, and fluid 
intake and output) to evaluate the 
subject’s hyponatremia state.
6)
A blood sample will be collected 
for serum sodium testing at 
12 hours post-dose.
7)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
8)
At the end of the Day 2 visit 
subjects will be assessed for 
response to tolvaptan treatment. 
Subjects who are:
a)
Responders (serum sodium 
level increase of 4 mEq/L 
[mmol/L]) will proceed to 
Treatment Phase B (see 
Section 3.7.1.3) for 
randomization.
b)
Nonresponders (serum 
sodium level increase of < 4 
mEq/L [mmol/L]) will 
proceed to Day 2a (see 
Section 3.7.1.2.3).
Throughout the visit
9)
Concomitant medications will be 
recorded.
10) Adverse events will be assessed.


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be performed.
8)
Body weight will be measured as 
possible.
9)
Subjects will be monitored and 
treated as clinically warranted per 
the investigator’s preferred 
standard of care for up to 
3 additional days after the last dose 
of tolvaptan (note:  the Early 
Withdrawal group should be 
monitored for the first 48 hours 
post-last dose).
10) Concomitant medications will be 
recorded.
11) Adverse events will be assessed.
3.7.1.4.2 Follow-up
1)
Subjects will be assessed for 
maintenance of normal or target 
serum sodium concentration at 
7 (1) days post-randomization.  
If the subject was discharged, 
he/she should return to the clinic 
for the serum sodium collection.
2)
A blood sample for serum sodium 
testing will be collected.
3)
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 the blood 
draws.
4)
A directed physical examination 
will be performed.
5)
A neurological examination will 
be performed.
6)
Body weight will be measured.
7)
Concomitant medications will be 
recorded.
8)
Adverse events will be assessed.
3.7.1.4.3 Follow-up Telephone 
Contact/Visit
Subjects (or their parents or legal 
guardians) will be contacted via telephone 
or via a visit 14 (+ 2) days post-
randomization to assess any new or 
ongoing AEs and to collect information on 
any medications administered since the last 
visit.  Ongoing follow-up may be required 
after trial closure for health status before 
the analysis of all trial results is completed.
3.7.1.2.3 Day 2a (optional)
The following procedures will be 
performed on Day 2a for all subjects who 
are not responsive to tolvaptan treatment at 
the end of Day 2.  
Predose
1)
Vital signs will be assessed at 24 
hours post-previous dose.  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 
the blood draws.
2)
A blood sample for STAT serum 
sodium testing should be taken at 
24 (4) hours post-previous dose 
and the results known prior to 
subsequent tolvaptan dosing.
3)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
4)
A directed physical examination 
will be performed.
5)
Body weight will be measured.
Dosing
6)
Tolvaptan will be administered. 
If the subject’s serum sodium 
concentration is < 135 mEq/L 
(mmol/L) and a 4 mEq/L 
(mmol/L) increase, tolvaptan dose 
should be adjusted per the titration 
guidelines (Section 3.2.4) for the 
assigned weight group.
Postdose
7)
Clinical status assessments will be 
performed per inpatient standard 
of care, ie, patient chart entries 
will be reviewed (including 
hyponatremia assessment notes, 
including laboratory results [trial 
and nontrial specific], any 
examination findings, medical 
problem list changes, and fluid 
intake and output) to evaluate the 
subject’s hyponatremia state.
8)
A blood sample will be collected 
for serum sodium testing at 
12 hours post-dose.
9)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
10) At the end of the Day 2a visit 
subjects will be assessed for 


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response to tolvaptan treatment. 
Subjects who are:
a)
Responders (serum sodium 
level increase of 4 mEq/L 
[mmol/L]) will proceed to 
Treatment Phase B (see 
Section 3.7.1.3) for 
randomization.
b)
Nonresponders (serum 
sodium level increase of < 4 
mEq/L [mmol/L]) will 
continue to Treatment Phase 
B where they either continue 
on tolvaptan therapy for 
2 additional days or are 
withdrawn from tolvaptan to 
be treated per the 
investigator’s preferred 
standard of care.
Throughout the visit
11) Concomitant medications will be 
recorded.
12) Adverse events will be assessed.
3.7.1.3.1 Day 3
The following procedures will be 
performed on Day 3. Some assessments are 
required for all subjects while other 
assessments only apply to certain subsets of 
subjects as indicated.
For all subjects (at trough)
1)
At trough (24 hours post-previous 
dose) the following assessments 
will be performed:
a)
Vital signs will be assessed.  
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 blood draws.
2)
Blood samples will be collected 
concurrently at 24 (4) hours for:
a)
STAT serum sodium testing 
and the results known prior to 
subsequent tolvaptan dosing. 
b)
PK analysis of tolvaptan
3)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
For all subjects classified as Responders 
at the end of Treatment Phase A


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4)
Randomize the subject to the 
Early or Late Withdrawal group 
using the trial’s interactive 
response system.
For subjects receiving tolvaptan (Late 
Withdrawal group and non-responders 
with continuing treatment)
5)
Body weight will be measured.
4)
Tolvaptan will be administered.
For subjects not receiving tolvaptan 
treatment (Early Withdrawal group and 
non-responders treated with standard of 
care)
6)
Early Withdrawal subjects will be 
observed to determine whether 
additional intervention is required 
to maintain appropriate serum 
sodium levels. 
3)
Nonresponders discontinuing 
tolvaptan will be treated per the 
investigator’s preferred standard 
of care.
For all subjects at later time points 
during the visit
4)
A directed physical examination 
will be performed.
5)
A neurological examination will 
be performed.
6)
A blood sample will be collected 
for serum sodium testing at 
12 hours post the nominal dosing 
time (regardless of treatment).
7)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
8)
Clinical status assessments will be 
performed per inpatient standard 
of care, ie, patient chart entries 
will be reviewed (including 
hyponatremia assessment notes, 
including laboratory results [trial 
and nontrial specific], any 
examination findings, medical 
problem list changes, and fluid 
intake and output) to evaluate the 
subject’s hyponatremia state.
For all subjects throughout the visit
9)
Concomitant medications will be 
recorded.
10) Adverse events will be assessed.


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3.7.1.3.2 Day 4
The following procedures will be 
performed on Day 4.  Some assessments 
are required for all subjects while other 
assessments only apply to certain subsets of 
subjects as indicated.
For subjects receiving tolvaptan (Late 
Withdrawal group and non-responders 
with continuing treatment)
At trough
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 
performed prior to blood draws.
2)
A blood sample for STAT serum 
sodium level testing should be 
taken and the results known prior 
to subsequent treatment.
3)
Blood samples for PK analysis of 
tolvaptan will be collected.
4)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
At later time points during the visit
5)
Body weight will be measured.
6)
Tolvaptan will be administered.
For subjects not receiving tolvaptan 
treatment (Early Withdrawal group and 
nonresponders treated with standard of 
care)
For all subjects at 48 hours post last 
dose
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 
performed prior to blood draws.
2)
A blood sample for serum sodium 
level testing should be taken.
3)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
At later time points during the visit
4)
Early Withdrawal subjects will be 
observed to determine whether 
additional intervention is required 
to maintain appropriate serum 
sodium levels. 
5)
Nonresponders discontinuing 
tolvaptan will continue to be 


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treated per the investigator’s 
preferred standard of care.
For all subjects at later time points 
during the visit
7)
A directed physical examination 
will be performed.
8)
A neurological examination will 
be performed.
9)
A blood sample will be collected 
for serum sodium testing at 
12 hours post the nominal dosing 
time (regardless of treatment).
10) A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
11) A QoL assessment will be 
conducted.
12) Clinical status assessments will be 
performed per inpatient standard 
of care, ie, patient chart entries 
will be reviewed (including 
hyponatremia assessment notes, 
including laboratory results [trial 
and nontrial specific], any 
examination findings, medical 
problem list changes, and fluid 
intake and output) to evaluate the 
subject’s hyponatremia state. 
For all subjects throughout the visit
13) Concomitant medications will be 
recorded.
14) Adverse events will be assessed.
3.7.1.3.3 Day 5
The following procedures will be 
performed on Day 5.  
For subjects receiving tolvaptan (Late 
Withdrawal group and non-responders 
with continuing tolvaptan treatment)
At trough
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 
performed prior to blood draws.
2)
A blood sample for STAT serum 
sodium level testing should be 
taken and the results known prior 
to subsequent treatment.


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3)
A blood sample for PK analysis of 
tolvaptan will be collected.
4)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
5)
Body weight will be measured.
Throughout the visit 
6)
Concomitant medications will be 
recorded.
7)
Adverse events will be assessed.
For subjects not receiving tolvaptan 
treatment (Early Withdrawal group and 
nonresponders treated with standard of 
care)
13) Proceed to Follow-up Phase C as 
for these subjects the 72h post-last 
dose time point (Section 3.7.1.4.1) 
falls on the morning of Day 5.
3.7.1.4 Follow-up Phase C
3.7.1.4.1 72 Hours Post-last Dose or ET
The following procedures will be 
performed for all subjects at 72 (4) hours 
post-last dose or at early termination (ET).  
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
performed prior to blood draws.
2)
Hematology, coagulation, and 
serum chemistry laboratory 
samples will be collected.
3)
For Early Termination only: 
Blood sample for PK analysis of 
tolvaptan will be collected at 24 
hours post-last dose for all 
subjects on tolvaptan.  The sample 
is to be taken concurrently with 
the serum sodium sample (part of 
the serum chemistry panel).  
4)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum chemistry sample.
5)
A directed physical examination 
will be performed.
6)
A neurological examination will 
be performed.
7)
Body weight will be measured.
8)
A urinalysis laboratory sample 
will be collected.
9) For Early Termination: Subjects 
will be monitored and treated as 


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clinically warranted per the 
investigator’s preferred standard of 
care for up to 3 additional days after 
the last dose of tolvaptan.
10)Concomitant medications will be 
recorded.
11) Adverse events will be assessed.
3.7.1.4.2 7 Days Post-last Dose
Subjects will be assessed for maintenance 
of normal or target serum sodium 
concentration at 7 (1) days post-last dose.  
All clinical labs will be performed locally.  
If the subject was discharged, he/she 
should return to the clinic for this 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 
performed prior to blood draws.
2)
A blood sample for serum sodium 
testing will be collected.
3)
A neurocognitive assessment will 
be performed within 1 hour of the 
serum sodium sample.
4)
A QoL assessment will be 
conducted.
5)
A directed physical examination 
will be performed.
6)
A neurological examination will 
be performed.
7)
Clinical status assessments will be 
performed per inpatient standard 
of care, ie, patient chart entries 
will be reviewed (including 
hyponatremia assessment notes, 
including laboratory results [trial 
and nontrial specific], any 
examination findings, medical 
problem list changes, and fluid 
intake and output) to evaluate the 
subject’s hyponatremia state.
8)
Body weight will be measured.
9)
Concomitant medications will be 
recorded.
7)
Adverse events will be assessed.
3.7.1.4.3 14 Days Post-last Dose
Subjects (or their parents or legal 
guardians) will be contacted via telephone 
or will be asked to come back to the clinic 
for a visit at 14 (+ 2) days post-last dose to 
assess any new or ongoing AEs and to 
collect information on any medications 


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administered since the last visit.  Ongoing 
follow-up may be required after a subject’s 
trial completion for health status before the 
analysis of all trial results is completed.
3.7.2.1 Serum 
Sodium 
Concentration
Monitoring frequency of serum sodium is at 
the discretion of the clinical investigator; 
however, the trial requires the minimum 
sample collection for all subjects noted in 
Section 3.7.1.
Within 48 hours of initial tolvaptan 
administration, 2 blood samples will be 
collected at least 12 hours apart for 
assessment of baseline serum sodium to 
determine subject eligibility.  A third 
(STAT) 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 STAT 
serum sodium sample should be drawn and 
recorded in the CRF at the time of every 
hyponatremia symptoms assessment 
(Section 3.7.1).  During Phase A, serum 
sodium will be assessed at 12 hours post-
first dose and 24 (4) hours post-previous 
dose.  Serum sodium must also be assessed 
at 12, 24, 36, 48, and 72 (4) hours and 
7 (1) days post-randomization.
Monitoring frequency of serum sodium is 
at the discretion of the clinical investigator; 
however, the minimum sample collection 
required for all subjects is described in 
Section 3.7.1.
In order to qualify for this trial, subjects 
must have documentation of chronic 
dilutional hyponatremia (serum sodium < 
130 mEq/L [mmol/L]) that is present for 
≥48 hours.  Specifically, each subject must 
have 2 blood samples collected at least 
12 hours apart over a minimum of 48 hours 
for assessment of baseline serum sodium 
level to determine subject eligibility.  
These can be either part of the recent 
medical history concerning the current 
hospital stay or prospectively collected as 
part of this trial.
On Day 1, a third (STAT) serum sodium 
sample should be drawn within 2-4 hours 
prior to dosing; the results must be verified 
to be < 130 mmol/L prior to the first dose.  
Serum sodium assessments should be 
performed at 8 hours post-first dose and at 
trough 24 hours post-first dose (this 
assessment will fall on Day 2 predose). 
On Day 2 (or 2a), Day 3, and Day 4 
(through the following morning on Day 5):

For all subjects receiving tolvaptan 
(Late Withdrawal and Nonresponders 
continuing on tolvaptan) serum sodium 
assessments will be performed at 
trough and 12 hours post-dose each day 
during Treatment Phase A and 
Treatment Phase B.

For all subjects not receiving tolvaptan 
(Early Withdrawal and Nonresponders 
on standard of care) serum sodium 
assessments will be performed every 
12 hours throughout Treatment Phase 
A and Treatment Phase B.  
For all subjects final serum sodium 
assessments will be taken at 24 (± 4) and 
72 (± 4) hours post-last dose as well as at 7 
days post-last dose.
3.7.2.3 Quality of Life Assessments
Two patient-reported outcomes instruments 
(acute versions with 7 day recall period) 


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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.  
The assessment time points are at 
screening, Day 4 and 7 days post-last dose.
3.7.2.4 Neurocognitive Assessments
An age-appropriate (4-18 years of age) 
neurocognitive assessment 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, 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.
3.7.3.1.1 Blood 
Collection 
Times

Tolvaptan plasma concentrations will 
be measured.  On Day 1, blood samples 
Blood samples will be taken so that 
tolvaptan and metabolite concentrations 
can be determined. Samples will be taken 


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(1 mL) for tolvaptan concentrations 
will be taken at 1, 2, 4, 12, and 24 
hours (5 minutes for each draw up to 
2 hours postdose and 30 minutes for 
later time points) post-first dose, at 
24 and 48 hours post-randomization 
(for subjects on tolvaptan in Phase B, 
including subjects who are deemed 
nonresponders and continue on 
tolvaptan), or at ET, if ET is before the 
last scheduled PK assessment.  Each 
subject contributing samples to the PK 
analysis will be required to submit a 
total 5 mL of blood in 24 hours and 2 
additional samples after randomization.
All samples will be collected from each 
subject according to local guidelines and 
best practices for pediatric care.
on Day 1 at 2 hours (5 minutes) and 8 
hours (concurrent with 8 h serum sodium 
sample) post-first dose.  On Days 2, 3, 4 
and 5 samples will be taken at trough (24 
hours post previous dose but prior to the 
subsequent dose), concurrent with serum 
sodium samples,  for subjects dosed with 
tolvaptan on Days 1, 2, 3, and/or 4, 
respectively, regardless of status as 
responder/non-responder. An early 
termination (ET) sample will be taken if 
ET occurs prior to the last planned PK 
sample. No ET sample is required if ET 
occurs at the same visit where a PK sample 
has already been obtained.
For each PK blood sample collected 
volumes are not expected to exceed 1.2 
mL. Total volume per sample may be lower 
depending on finalization of blood 
collection supplies.  
Serum sodium assessments and other 
clinically necessary blood samples take 
priority, therefore, due to restrictions in 
allowable total daily blood volumes based 
on local guidelines and subject age, it may 
not be possible to take more than one PK 
sample per day. If so, the PK sampling 
should be changed to:

Day 1: 2 hours post dose (5 
minutes)

Day 2: 8 (2) hours post dose (may 
be concurrent with serum sodium or 
other blood sampling)

Day 3 at trough, ie, pre-dose/24 hours 
post prior dose (concurrent with 
serum sodium sample)
For each subject all samples will be 
collected according to local guidelines and 
best practices for pediatric care.  If a 
sample is missing due to limitations in 
allowable blood volumes based on local 
regulations or local practice this will not 
count as a protocol deviation.
3.7.3.3
3.7.3.3.1 Fluid Balance (Intake/Output)
Fluid intake (both oral and IV) and urine 
volume will be measured at the times 
presented in the schedule of assessments 
(Section 3.7.1).  The fluid content of foods 
with significant water content (eg, soup) 
should be added to the total fluid intake.  
Fluid balance will be monitored per 
institutional guidelines.
3.7.3.3.2 Laboratory Tests
3.7.3.2.1 Fluid Intake
Fluid intake (both oral and IV) will be 
measured at the times presented in the 
schedule of assessments (Section 3.7.1).  
The fluid content of foods with significant 
water content (eg, soup) should be added to 
the total fluid intake.  Fluid intake will be 
monitored per institutional guidelines.
3.7.3.2.2 Urine Volume


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Urine chemistry will be determined in urine 
samples that will be collected at the 
intervals presented in the schedule of 
assessments, Section 3.7.1.  The list of 
urine chemistry tests to be collected is 
presented in Table 3.7.4.2-1.  All urine 
voids within a collection interval will be 
kept refrigerated and at the end of the 
collection interval, the samples pooled 
together, the urine volume determined, and 
an aliquot taken according to instructions 
from the clinical chemistry laboratory.
Urine volume will be determined in urine 
samples that will be collected at the 
intervals presented in the schedule of 
assessments, Section 3.7.1.  All urine voids 
within a collection interval should be kept 
refrigerated and pooled according to the 
size of available collection containers. At 
the end of the collection interval all 
samples should be pooled and the urine 
volume determined.  
3.7.3.2.3 Urine Chemistry
Urine chemistry will be determined from 
pooled urine samples collected for the 
intervals presented in the schedule of 
assessments, Section 3.7.1.  An aliquot will 
be taken for each collection interval 
according to the procedures of the local 
clinical chemistry laboratory. The list of 
urine chemistry tests to be conducted is 
presented in Table 3.7.4.2-1.
3.7.4 Safety 
Assessments
3.7.4.1 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 
> 8mmol/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 detail).
In addition, active monitoring is required 
for:

Absolute serum sodium level 
145 mEq/L (mmol/L) or an overly 
rapid rise in serum sodium level (an 
increase in serum sodium of 
> 8 mEq/L [mmol/L] over a 10-hour 
period, 12 mEq/L [mmol/L] over a 
24-hour period, or a rate of increase in 
serum sodium concentration that the 
investigator deems too rapid), 
neurological 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 total bilirubin level should 
also be evaluated.  See Section 3.7.4 
for more information and Section 5.4.1
for detailed instructions on how this 
type of event should be captured.

Worsening symptoms of hyponatremia

Hypovolemia or hypotension requiring 
intervention


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3.7.4.2.1 Serum Osmolality
Serum osmolality will be calculated to help 
guide dosing.  Local site personnel will 
determine serum osmolality using one of 
the following equations:
a)
Where Na, glucose, and BUN are 
measured in mg/dL:
Serum Osmolality (mOsm/kg) = 2 Na 
+ BUN / 2.8 + (glucose / 18)
b)
Where Na, glucose, and urea are 
measured in mmol/L:
Serum Osmolality (mOsm/kg) = 2 Na 
+ glucose + urea
3.7.4.1.1 
Clinical 
Laboratory 
Tests
Table 3.7.4.2-1 presents the protocol-
required clinical laboratory results (serum 
chemistry, hematology, coagulation, 
urinalysis, and urine chemistry) that will be 
reported as part of the trial results.  Serum 
cortisol and TSH will be measured at the 
Screening/Baseline Visit using the 
remaining blood sample obtained for serum 
chemistry….assessments (Table 3.7-1).
Table 3.7.4.2-1 presents required clinical 
laboratory assessments (serum chemistry, 
hematology, coagulation, urinalysis, and 
urine chemistry).  All clinical laboratory 
tests will be performed by local 
laboratories.  Serum cortisol and TSH will 
be measured during screening using the 
remaining blood sample obtained for serum 
chemistry….assessments (Section 3.7.1).  
Uric acid will be measured during 
screening for calculation of FENa and FE 
urate.
WBC = white blood cell; RBC = red blood 
cell.
In case of limited blood or urine volume 
availability the bolded assessments take 
priority. Serum Sodium and liver function 
tests are essential to the conduct of the trial.
3.7.4.2.3 
Monitoring of 
Liver Tran-
saminases
…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 CRFs.  See 
Section 5.4.1 for detailed instructions on 
how this type of event should be captured.
…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 total bilirubin level 
should also be evaluated.  These elevated 
values should be confirmed by retesting.  If 
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 CRFs.  
See Section 5.4.1 for detailed instructions 
on how this type of event should be 
captured.
3.7.4.3 Physical 
Examination
All physical examination assessments 
should include assessments of all major 
All physical examination assessments 
should include assessments of all major 


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body systems, including but not limited to, 
ears, nose, and throat, the thorax area, 
abdomen, urogenital, extremities, and skin 
and mucosae. Neurological examinations 
will be performed in an age-appropriate 
manner per Section 3.7.4.4.
Body weight will be measured predose each 
day,…
body systems, including but not limited to, 
ears, nose, and throat, the thorax area, 
abdomen, urogenital, extremities, and skin 
and mucosae.  Neurological examinations 
will be performed in an age-appropriate 
manner per Section 3.7.4.3.1. ...
Body weight will be measured predose 
each day throughout Treatment Phase A, 
Treatment Phase B and at each clinic visit 
in Follow-up Phase C…
3.7.4.4 Tanner 
Staging
Tanner Staging will 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 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 
investigator will arrive at a single score 
summarizing the domains (not individual 
domain scores) when evaluating the 
subject.
3.7.4.5 Vital 
Sign 
Assessments
Vital sign data (including supine blood 
pressure, heart rate, respiratory rate, and 
temperature) will be performed and 
documented according to Section 3.7.1 of 
this protocol.  Supine vital signs will be 
taken when the subject has been lying down 
(bed positioned < 45 degree angle) for at 
least 3 minutes.  All post-baseline 
assessments for vital signs should be 
performed around the time of the formal 
hyponatremia assessment during tolvaptan 
dosing and anytime during the Follow-up 
Visits consistent with the timing of other 
trial assessments.  All vital sign 
assessments should be performed prior to 
the blood draw at the nominal time point.
Vital signs (including supine blood 
pressure, heart rate, respiratory rate, and 
temperature) will be assessed at time points 
according to Section 3.7.1 of this protocol.  
Supine vital signs will be taken when the 
subject has been lying down (bed 
positioned < 45 degree angle) for at least 3 
minutes.  All assessments for vital signs 
should be performed around the time of the 
formal hyponatremia assessment (sodium 
blood draw) during Screening, Treatment 
Phase A and Treatment Phase B and 
anytime during the Follow-up Period 
consistent with the timing of other trial 
assessments.  All vital sign assessments 
should be performed prior to the blood 
draw at the nominal time point.
3.7.4.6 Fluid 
Restriction
In subjects with chronic hyponatremia, 
fluid restriction coadministered with 
initiation of treatment with a vaptan has the 
potential to accentuate the rate of sodium 
correction and to cause overly rapid 
correction or over correction of 
hyponatremia.  Therefore, during treatment, 
subjects must have access to water and 
maintain fluid intake levels per institutional 
guidelines.  Fluid restriction during the first 
48 hours after discontinuation of tolvaptan 
will be considered rescue therapy.
3.9 Screen 
A screen failure subject is one from whom A screen failure subject is one from whom 


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Failures
informed consent/assent (if applicable) is 
obtained and is documented in writing (ie, 
the subject’s parent or legal guardian signs 
an ICF), but who is not enrolled into the 
trial.…
informed consent/assent (if applicable) has 
been obtained and is documented in writing 
(ie, the subject’s parent or legal guardian 
signs an ICF), but who is not enrolled into 
the trial.  If a subject’s serum sodium level 
during the Screening period is 130 
mEq/L [mmol/L], that subject will be 
determined a screen failure.…
3.10 Definition 
of Completed 
Subjects
The treatment period is defined as the time 
period during which subjects are evaluated 
for primary and/or secondary objectives of 
the trial irrespective of whether or not the 
subject actually consumed all doses of the 
IMP.  Subjects who are evaluated at the last 
scheduled visit during the treatment period 
will be defined as trial completers.  For 
purposes of this trial, subjects who 
complete the final Follow-up Visit at 
14 days post-randomization will be defined 
as trial completers.
The treatment period is defined as the time 
period during which subjects are evaluated 
for primary and/or secondary objectives of 
the trial irrespective of whether or not the 
subject actually consumed all doses of the 
tolvaptan.  
For purposes of this trial, subjects who are 
randomized responders and who complete 
required trial assessments (including their 
assigned trial treatment) through the end of 
the trial will be defined as responder trial 
completers. 
For purposes of this trial, subjects who are 
nonresponders (not randomized) but who 
complete required trial assessments through 
the end of the trial will be defined as 
nonresponder trial completers. 
Subjects who discontinue tolvaptan prior to 
the end of Treatment Phase B, but who 
continue in the trial and complete some or 
all of their required assessments to the end 
of the trial, will be considered “early” end 
of treatment (EEOT) completers.
4.2 Other 
Restrictions
…The use of saline in this population 
should be closely monitored.  The use of 
hypertonic saline (3%) within 8 hours of the 
initial screening laboratory collection is 
prohibited.
Please see Section 3.4.3 for the list of 
prohibited medications.  The use of normal 
saline (0.9%) is allowed during the 
Screening Period until the beginning of 
Phase A; normal saline use can resume in 
Phase C.  Subjects should no longer be on 
maintenance fluids containing normal 
saline during treatment with tolvaptan.  
…Other treatment for the purpose of 
increasing serum sodium, eg with urea, 
lithium, demeclocycline, conivaptan or 
tolvaptan, concurrent with dosing of trial 
medication or within 4 days of qualifying 
serum sodium assessments at screening is 
prohibited.
The use of saline in this population should 
be closely monitored.  The use of 
hypertonic saline (3%), including normal 
saline challenge) within 8 hours of the 
qualifying screening serum sodium 
laboratory assessment is prohibited.
The use of normal saline (0.9%) is allowed 
during screening until the beginning of 
Treatment Phase A; normal saline use can 
resume in Phase C.  Subjects should no 
longer be on maintenance fluids containing 
normal saline during treatment with 


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tolvaptan.  
5.1 Definitions
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.
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 criteria is 
provided in Section 5.1.  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 total 
bilirubin level should also be evaluated.  
Elevated values should be confirmed via 
retest.  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.
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 level should 
also be evaluated….
The following guideline for repeat testing 
may be used by investigators as a reference 
for any subject with an ALT or AST 3 
ULN:
2)Inquiries should be made about 
symptoms (fatigue, nausea, vomiting, 
right upper quadrant pain or 
tenderness, fever, and/or rash).
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 total bilirubin level should 
also be evaluated….
The following guideline for repeat testing 
may be used by investigators as a reference 
for any subject with an ALT or AST 2 
ULN:
2) Inquiries should be made about 
symptoms (fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, 
and/or rash) and signs like jaundice, 


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yellowish discoloration of sclera, etc
5.4.1.1 Criteria 
for Discon-
tinuation 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 3 ULN with appearance 
of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%)
A subject must be discontinued from the 
trial on confirmation of any of the 
following criteria:
1) 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
5.7 Follow-up of 
Adverse Events
For this trial, information on AEs will be 
followed for up to 14 days post-
randomization.
For this trial, information on AEs will be 
followed for up to 14 days post-last dose 
for all subjects or until resolution, 
whichever is longer.
5.7.2 Follow-up 
of Post Trial 
Serious Adverse 
Events
This trial requires that subjects be actively 
monitored for SAEs up to 14 days 
post-randomization.
This trial requires that subjects be actively 
monitored for SAEs up to 14 days post-last 
dose or until resolution of the SAE, 
whichever is longer.
6.1 Pharmaco-
kinetic Analysis
Tolvaptan plasma concentrations will be 
summarized using descriptive statistics (n, 
median, mean, standard deviation [SD], 
percent coefficient of variation [CV], 
minimum, and maximum) by dose group 
and time point.
Tolvaptan and metabolite plasma 
concentrations will be summarized using 
descriptive statistics (n, median, mean, 
standard deviation [SD], percent coefficient 
of variation [CV], minimum, and 
maximum) by dose group and time point.
6.2 Pharmaco-
dynamic 
Analysis
… Fluid intake and the calculated value of 
fluid balance will be summarized for each 
6-hour period on Days 1 and 2 (Phase A) 
using descriptive statistics….
Urine osmolality and urine creatinine, 
potassium, uric acid, and sodium 
concentrations will be summarized by 
collection interval and for zero to 24 hours 
on Days 1 and 2 (Phase A) using 
descriptive statistics….
… Fluid intake and the calculated value of 
fluid balance will be summarized for each 
6-hour period and for the 24-hour daily 
interval on Days 1 and 2 in Treatment 
Phase A using descriptive statistics…
Urine osmolality and urine creatinine, 
potassium, and sodium concentrations will 
be summarized by collection interval and 
for zero to 24 hours on Days 1 and 2 in 
Treatment Phase A using descriptive 
statistics…
Correlations between tolvaptan AUC 
values and urine output on Day 1 may be 
explored graphically
7.1.1 Sample 
Size for Efficacy
A total of 70 randomized subjects will 
provide 90% power to detect a treatment 
difference of 4 mmol/L in change in serum 
sodium from randomization (at the end of 
Day 2/3 [Phase A]) to the end of Day 4/5 (2 
days after randomization [Phase B]) using a 
2-sided alpha of 0.05.  An SD of 5 in 
change of serum sodium was used for the 
sample size calculation.  After the end of 
treatment at Day 2/3, subjects will be 
randomized at a ratio of 1:1 to either 
continue treatment with tolvaptan for 2 
additional days (Late Withdrawal) or to 
discontinue tolvaptan treatment (Early 
A total of 70 randomized subjects will 
provide 90% power to detect a treatment 
difference of 4 mEq/L (mmol/L) in change 
in serum sodium from Day 2 (or 2a) at the 
end of Treatment Phase A to the end of 
Treatment Phase B using a 2-sided alpha of 
0.05.  An SD of 5 in change of serum 
sodium was used for the sample size 
calculation.  After the end of Treatment 
Phase A at Day 2 (or 2a), subjects will be 
randomized at a ratio of 1:1 to either 
continue treatment with tolvaptan for 2 
additional days (Late Withdrawal) or to 
discontinue tolvaptan treatment (Early 


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Withdrawal).  Sample size re-estimation 
will be conducted when 90% of the subjects 
finish (complete or discontinue) the trial.
Withdrawal).  Sample size re-estimation 
will be conducted when 90% of the 
subjects finish (complete or discontinue) 
the trial.
7.4.2.2 Safety
Other secondary endpoints include:

Percentage of subjects with overly 
rapid increase in serum sodium (
12mmol/L in 24 hours after the first 
dose).

Percentage of subjects requiring rescue 
medication during Phase A and Phase 
B of the trial.

Change in serum sodium from 24 hours 
post-last dose to 14 days 
post-randomization.

Vital signs, blood pressure, clinical 
laboratory tests, and body weight.
Other secondary endpoints include:

Percentage of subjects with overly 
rapid increase in serum sodium level 
(
 
).

Change in serum sodium level from 24 
hours post-last dose to 7 days post-last 
dose.

Percentage of subjects requiring rescue 
therapy (other than fluid restriction) 
during Treatment Phase A and 
Treatment Phase B.

Percentage of subjects requiring fluid 
restriction during Treatment Phase A 
and Treatment Phase B.

Other secondary safety outcomes to be 
assessed are presented in Section 
3.5.3.1 (Vital signs, blood pressure, 
clinical laboratory tests, body weight, 
and neurological examinations)
7.4.3 
Exploratory 
Outcome 
Analysis
Neurological examination data will be 
presented in the data listings.
The change in serum sodium concentration 
in nonresponders continuing on tolvaptan 
therapy by change from baseline at the end 
of Treatment Phase B compared to the end 
of Treatment Phase A will be analyzed 
using a paired Student’s t-test.  
The procedure for the analysis of data for 
the neurocognitive and QoL assessments 
will be provided in the SAP.
The analysis for the following exploratory 
PD endpoints is described in Section 6.2:

In all subjects, 24-hour excretion of 
sodium, creatinine, and osmolality on Days 
1 and 2

24-hour sodium clearance on Day 1
14 References
26 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/
GuidanceComplianceRegulatoryInfor
mation/Guidances/UCM174090.pdf.
27 U.S. Food and Drug Administration. 
[available on the internet, last updated 
22Jan2014; cited 14Feb2014]. 
Available from: 
http://www.fda.gov/Drugs/ 
ScienceResearch/ResearchAreas/ucm0


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71471.htm
Appendix 1: 
Names of 
Sponsor 
Personnel: IRE
Country
Safety Fax Numbers
Country
Safety Fax Numbers
United 
States 
 (primary) or 
 (alternative)
Australia
Argentina
Belgium
Australia
Canada 
 (primary) 
or 
 
(alternative)
Belgium
Czech Republic
Canada 
 (primary) or 
 (alternative)
Germany
Colombia
Italy
Czech 
Republic
Netherlands
Finland
Peru
France
Poland
Georgia
No toll free number available; 
please dial 
 
(primary) or 
 
(alternative)
Romania
Germany
Spain
Hong Kong
Turkey
No toll free number 
available;  please dial 
 (primary) 
or 
 
(alternative)
Israel
United 
Kingdom
Italy
United States 
 (primary) 
or 
 
(alternative)
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)


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Ukraine
United 
Kingdom
 
:
 
 
Medical 
Monitor:
Phone 
; Mobile 
E-Mail 
Back-up:
Phone 
; Mobile 
E-Mail 
Europe/Rest of World:
Phone 
E-Mail 
3201 Beechleaf Court, Suite 600
Raleigh, North Carolina 27604 USA
Phone 
 
Mobile 
E-Mail 
Institutions 
Concerned 
With the Trial:
Study Communications & Patient/Site
Support
BBK Worldwide
117 Kendrick Street, Suite 600
Needham, Massachusetts 02494, US
Phone: 
Study Communications & Patient/Site
Support
Mathews Media Group 
700 King Farm Boulevard, Suite 500
Rockville, MD 20850, USA
Phone: 
Central Laboratory (non-PK)
Covance Central Laboratory Services
8211 SciCor Drive
Indianapolis, Indiana 46214, US
Phone:  
Clinical Laboratory Supplies
Covance Central Laboratory Services
8211 SciCor Drive
Indianapolis, Indiana 46214, USA
Phone:  
Neurocognitive Battery
Cogstate, Ltd.
195 Church Street
8th Floor
New Haven, CT 06510 USA


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ADDITIONAL RISK TO THE SUBJECT:  There is no additional risk to the subjects.


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Issue Date:
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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.

Clarification of the “baseline” assessment for trial qualification.

Additional background data from non-clinical juvenile toxicity studies.

Updates to clarify the titration and rescue therapy schematic.

Clarify roll-over into extension study 156-11-294. 

Implementation of a suspension formulation for short-term use in hospitalized 
subjects.

Implementation of an optional swallow test for the tablet formulation.
BACKGROUND:
This protocol serves as the single trial for the Pediatric Written Request with the FDA 
and the Pediatric Research Equity Act (PREA) requirement for the US.  The FDA has 
agreed to the current version of the protocol and updates have been made to address 
further 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:
03 Jul 2013
Date of Amendment 1:
04 Nov 2013
Date of Amendment 2:
19 May 2014
Issue Date:
03 Jul 2013
Date of Amendment 1:
04 Nov 201
Date of Amendment 2:
19 May 2014
Date of Amendment 3:
26 February 2015
Protocol Synopsis 
Trial Design:
This is an open-label, multicenter, multiple-dose, randomized 
withdrawal, parallel-group trial of tolvaptan in children and 
adolescent subjects hospitalized with euvolemic or 
hypervolemic hyponatremia.
The trial will be conducted in two stages. The first stage will 
be conducted using the available tablet formulation of 
tolvaptan whereas the second stage will expand to include the 
use of a suspension once that formulation becomes available.
...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 this protocol, persistent hyponatremia will be 
defined as serum sodium assessments < 130 mEq/L (mmol/L) 
documented as present for at least 48 hours.  Specifically, 
subjects must have at least 2 documented serum sodium 
assessments < 130 mEq/L (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 mEq/L 
(mmol/L), which will serve as the baseline value for efficacy 
This is an open-label, multicenter, multiple-dose, randomized 
withdrawal, parallel-group trial of tolvaptan in children and 
adolescent subjects hospitalized with euvolemic or hypervolemic 
hyponatremia.
...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 this 
protocol, persistent hyponatremia will be defined as serum sodium 
assessments < 130 mEq/L (mmol/L) documented as present for at 
least 48 hours.  Specifically, subjects must have at least 2 
documented serum sodium assessments < 130 mEq/L (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 mEq/L (mmol/L), which will serve as the baseline value for 
final trial qualification and clinical management strategy, is to be 
obtained within 2-4 hours prior to the first dose of tolvaptan.  
Additional qualification assessments will be performed as per 
etiology of hyponatremia.  The first dose of tolvaptan will be 
administered upon successful completion of all screening 
procedures.


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endpoints, is to be obtained within 2-4 hours prior to the first 
dose of tolvaptan.  Additional qualification assessments will 
be performed as per etiology of hyponatremia.  The first dose 
of tolvaptan will be administered upon successful completion 
of all screening procedures.
...All Subjects
All subjects will have serum sodium levels measured at 8, 12, 
and 24 hours post-first dose and thereafter every 12 hours 
through completion of Treatment Phase B.  
...All Subjects
All subjects will have serum sodium levels measured at 8, 12, and 
24 hours post-first dose and thereafter every 12 hours through 
completion of Treatment Phase B.  In addition to serum sodium 
samples obtained for treatment qualification and efficacy 
endpoints, supplemental samples for the purposes of safety 
assessment will be obtained 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.
Protocol Synopsis 
Subject Population:
This trial will include up to 100 male and female subjects 
aged 4 weeks (or 44 weeks adjusted gestational age) to < 
18 years who have been diagnosed with euvolemic or 
hypervolemic hyponatremia (< 130 mEq/L [mmol/L]) that 
persists despite initial standard background therapy (including 
fluid restriction and excluding a vasopressin antagonist). Age 
groups will be enrolled such that 50% of these subjects will 
be < 10 years old and at least 25% of subjects < 6 years old.  
This trial will enroll approximately 100 male and female subjects 
to get approximately 70 randomized subjects aged 4 weeks (or 
44 weeks adjusted gestational age) to < 18 years who have been 
diagnosed with euvolemic or hypervolemic hyponatremia 
(< 130 mEq/L [mmol/L]) that persists despite initial standard 
background therapy (including fluid restriction and excluding a 
vasopressin antagonist).  Age groups will be enrolled such that at 
least 50% of these subjects will be < 10 years old and at least 25% 
of subjects < 6 years old.  
Protocol Synopsis 
Inclusion/Exclusion 
Criteria:
Key inclusion criteria:
Persistent euvolemic or hypervolemic hyponatremia defined 
as being documented as present for at least 48 hours, 
Key inclusion criteria:
Persistent euvolemic or hypervolemic hyponatremia defined as 
being documented as present for at least 48 hours, evidenced by at 


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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 2-4 
hours prior to the first dose of tolvaptan
Key exclusion criteria:
Use of potent cytochrome P450 (CYP) 3A4 inhibitors in 
subjects 50 kg or moderate CYP3A4 inhibitors in subjects < 
20 kg
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 final trial qualification and 
clinical management strategy, is to be obtained 2-4 hours prior to 
the first dose of tolvaptan
Key exclusion criteria:
Use of potent cytochrome P450 (CYP) 3A4 inhibitors in subjects 
< 10 kg or moderate CYP3A4 inhibitors in subjects < 6 kg
Protocol Synopsis 
Trial Sites:
The trial will be conducted at up to 50 centers globally.
The trial will be conducted at approximately 60 centers globally.
Protocol Synopsis 
Investigational 
Medicinal Product, 
Dose, Formulation, 
Mode of 
Administration:
Tolvaptan will initially be supplied as 3.75-, 7.5-, 15-, and 
30-mg spray-dried tablets.  Upon the availability of an oral 
suspension 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 of tolvaptan will be 
given with 60 mL of water.  The treatment duration will be up 
to 5 days.  Any initiation or titration of tolvaptan must occur 
in a hospital setting.
Tolvaptan will be supplied as 3.75-, 7.5-, 15-, and 30-mg 
spray-dried tablets and, where approved, as a 1 mg/mL (0.1% w/v) 
suspension.  
Tolvaptan tablets 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 of tolvaptan will be 
given with 60 mL of water.  The treatment duration will be up to 
5 days.  Any initiation or titration of tolvaptan must occur in a 
hospital setting.


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...
Subjects < 2 years of age, weighing < 10 kg, or who cannot 
safely swallow the tablet will be excluded until the 
availability of a suspension formulation.  
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 
Day 1 with possible up-titration to 30- and 60-mg doses.
Tolvaptan suspension will be administered once daily, orally using 
the provided, appropriately-sized syringe (3 mL or 10mL) to 
measure the volume.  The lowest volume that can be administered 
is 0.3 mL (0.3 mg).
The investigator has the option of performing a swallow test and 
providing coaching on swallowing techniques using placebo 
tablets if it is known or suspected that the subject is unable to 
swallow tablets.  Placebo tablets will be provided for use in 
performing this test at screening.
...
Subjects < 2 years of age, weighing < 10 kg will be given a 0.1 
mg/kg dose of the suspension on Day 1 with possible up-titration 
to 0.2 mg/kg and 0.4 mg/kg doses.
Subjects 2 years of age, weighing 10 to < 20 kg and who can 
safely swallow a tablet  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, and who can safely 
swallow a tablet,  will be given a 7.5-mg tablet on Day 1 with 
possible up-titration to 15- and 30-mg doses.
Subjects ≥ 2 years of age, weighing ≤ 30 kg and who cannot safely 
swallow a tablet, can be given a 0.15 mg/kg dose of the 
suspension on Day 1 with possible up-titration to 0.3 mg/kg and 
0.6 mg/kg doses.
Subjects weighing > 50 kg will be given a 15-mg tablet on Day 1 


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with possible up-titration to 30- and 60-mg doses.
Protocol Synopsis 
Trial Duration:
Overall trial duration of enrollment is expected to be 36 
months with an enrollment rate of 33 subjects per year.  
Nominal trial duration for each subject is up to 21 days.  
Treatment duration is up to 5 days with ongoing monitoring 
of serum sodium levels.  A serum sodium assessment and AE 
follow-up visit will be performed 7 (1) days post-last dose.  
A final safety follow-up telephone contact or visit will be 
performed 14 (+ 2) days post-last dose.
Overall trial duration of enrollment is expected to be 
approximately 3 years with an enrollment rate of approximately 33 
subjects per year.  Nominal trial duration for each subject is up to 
21 days.  Treatment duration is up to 5 days with ongoing 
monitoring of serum sodium levels.  A serum sodium assessment 
and AE follow-up visit will be performed 7 (1) days post-last 
dose.  A final safety follow-up telephone contact or visit will be 
performed 14 (+ 2) days post-last dose.
List of Abbreviations 
and Definitions of 
Terms:
Added 5 terms: EMA, MHRA, PDCO, PREA, and WOCBP
EMA European Medicines Agency
MHRA Medicines and Healthcare Products Regulatory
PDCO Paediatric Committee
PREA Pediatric Research Equity Act
WOCBP Women of child-bearing potential
1.1.1 Juvenile Animal 
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 1000 mg/kg/day and tolerable at 100 mg/kg/day and lower.
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 1000 
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 


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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.16 
1.2.1 
Pharmacokinetics:
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 Argentina, China, 
Japan, Republic of Korea, the United Kingdom (UK), and the 
US.16 
Following IV dosing, the terminal-phase elimination half-life 
(t1/2,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 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.16
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.  
Since inception of the program, a total of 53 clinical 
pharmacology trials have been completed with tolvaptan (as of 11 
Jul 2013) in healthy subjects or special populations in Argentina, 
China, Japan, Republic of Korea, the United Kingdom (UK), and 
the US.16
In healthy subjects, following IV dosing, the terminal-phase 
elimination half-life (t1/2,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 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.16 
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 


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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.16 
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%.16
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 
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.16 
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%).
In healthy subjects, tolvaptan pharmacokinetics following a 15 mg 
dose as a 1mg/mL suspension shows a more rapid absorption (the 
median tmax is shorter, 1.00 versus 2.00 hours respectively), when 
compared to a 15 mg tablet.  The geometric mean ratio (90% CI), 
for suspension over the tablet, for Cmax is 1.614 (1.484 to 1.754) 
but AUC is unchanged.
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%.16
Once a day dosage regimen trials in CHF subjects with 
extracellular volume expansion showed that tolvaptan 
concentrations increased less than proportionally with dose upon 


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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.16 
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).16
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 
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.16
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).16
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 


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at steady state, tolvaptan Cmax and AUCt are decreased 83% 
and 87%, respectively.16 
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.32,33
juice.  Following coadministration with 600 mg once daily 
rifampin at steady state, tolvaptan Cmax and AUCt are decreased 
83% and 87%, respectively.16
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.32,33
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 
1.2.2 
Pharmacodynamics:
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 
serum osmolality, and increased plasma AVP concentrations 
and renin activity, but no dose-related increases were 
1.2.2   Pharmacodynamics
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 


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observed for any other parameter.16 
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.16
Details of the currently available PK/PD data for the 
compound are available in the investigator’s brochure (IB).16
serum sodium and serum osmolality, and increased plasma AVP 
concentrations and renin activity, but no dose-related increases 
were observed for any other parameter.16 
When compared to a 15-mg spray-dried tablet, the 
pharmacodynamic profiles of urine excretion rate, cumulative 
urine volume, free water clearance, urine osmolality, and serum 
sodium were not different for 15-mg of the suspension.16
Details of the currently available PK/PD data for the compound 
are available in the investigator’s brochure (IB).16
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.16
The most commonly reported treatment-emergent adverse 
events (TEAEs; > 10% and greater than placebo) in healthy 
As of 31 Mar 2013, 6,794 adult subjects have been exposed to oral 
doses of tolvaptan spray-dried tablets 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.  Fourteen 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.16  As of 31 Mar 
2014, additionally, 14 healthy adult subjects were also exposed to 
the tolvaptan suspension formulation.
The most commonly reported treatment-emergent adverse events 


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subjects treated with tolvaptan were thirst, pollakiuria, and 
headache.  The most commonly reported 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, and nausea.  The IB 
provides a thorough review of the adverse events (AEs) 
experienced with this compound during clinical trials.16
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.
(TEAEs; > 10% and greater than placebo) in healthy subjects 
treated with tolvaptan were thirst, pollakiuria, and headache.  The 
most commonly reported 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, 
and nausea.  The IB provides a review of the adverse events (AEs) 
experienced with the spray-dried tablet and suspension 
formulation of tolvaptan during clinical trials.16
There is the potential for osmotic diarrhea due to the sorbitol 
content in the suspension.  D-Sorbitol is a hexahydric sugar 
alcohol that naturally occurs in fruits and animal tissue.  The daily 
per capita consumption of sorbitol as a food ingredient is 
approximately 200mg.  The compound is about 35-60% as sweet 
as sugar, and has been the impetus as a substitute for sugar to 
reduce caloric intake and prophylactic measures against the 
formation of dental caries.  Absorption of sorbitol by humans is 
limited by its rate of diffusion from the gastrointestinal tract and 
by laxation that may occur after ingestion of high doses.  
Typically, 25-50 g in adults may cause osmotic diarrhea.  The 
corresponding dose in children is thought to be 10 g and higher, 
but is dependent on body weight and types of foods ingested.  
Similar findings are also observed with other sugar alcohols, eg, 
xylitol.17 
Following a single 15 mg tolvaptan dose of the suspension, 


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containing 8 g of sorbitol, in healthy adults, no diarrhea was 
reported.34 
Therefore, in this trial, suspension dosing is limited to subjects 
who weigh ≤30 kg; the maximum dose of sorbitol is expected to 
be approximately 9.6 grams in a 0.6 mg/kg dose for a subject who 
weighs 30 kg. Subjects will be started on the lowest dose for their 
weight and titrated to higher doses as appropriate for their clinical 
condition.  Subjects will be in a hospital setting during titration 
and will be closely monitored for rate of sodium correction and 
signs of dehydration including diarrhea. 
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.
2.1 Trial Rationale:
The proposed population size of 100 subjects is expected to 
yield 70 subjects who respond to tolvaptan (henceforth termed 
“responders”), which has adequate power (> 90%) to test for 
statistical significance in the primary endpoint.  Enrollment is 
expected to take 3 years using up to 50 sites globally.  
Additional blood sampling will be included across 
populations to provide PK information.
The proposed population size of 100 subjects is expected to yield 
70 subjects who respond to tolvaptan (henceforth termed 
“responders”), which has adequate power (> 90%) to test for 
statistical significance in the primary endpoint.  Enrollment is 
expected to take approximately 3 years using approximately 60 
sites globally.  Additional blood sampling will be included across 
populations to provide PK information.


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Even with a limited size, recruitment for such a trial is 
expected to be challenging due to the low frequency of AVP-
mediated hyponatremia in children.  Therefore, the trial will 
be organized at major pediatric referral centers to access the 
largest patient population.
Even with a limited size, recruitment for such a trial is expected to 
be challenging due to the low frequency of AVP-mediated 
hyponatremia in children.  Therefore, the trial will be organized at 
major pediatric referral centers to access the largest patient 
population.
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.19 
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.20 
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.
2.1.1 Dosing 
Rationale:
Enrolled subjects will be dosed based on age, weight, and the 
use of CYP3A4 inhibitors.  Subjects < 2 years of age or < 10 
Enrolled subjects will be dosed based on formulation type, age, 
weight, and the use of CYP3A4 inhibitors.


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kg will be excluded until the availability of an oral suspension 
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.
In the pivotal hyponatremia trials16,21,22 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 2.1.1-1 outlines 
the mg/kg dose ranges for tolvaptan tablet doses and body 
weights of 10, 20, 50, 70 (standard adult man), and 100 kg.
...Tolvaptan is a sensitive CYP3A4 substrate; plasma 
concentrations increased approximately 4-fold when tolvaptan 
was administered with the potent CYP3A4 inhibitor 
ketoconazole.16,24  Where appropriate dose reductions are 
possible, tolvaptan doses may be coadministered with potent
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 use of tolvaptan tablets in this 
trial were selected to produce mg/kg doses of tolvaptan within the 
range observed for the adult trials. Table 2.1.1-1 outlines the 
mg/kg dose ranges for tolvaptan tablet doses and body weights of 
10, 20, 50, 70 (standard adult man), and 100 kg.
...Tolvaptan is metabolized by the CYP3A isozyme.  At birth, the 
amount per gram liver of CYP3A is less than in an adult but adult 
levels of CYP3A are reached by 2 years of age.  A 
physiologically-based pharmacokinetic model of adult tolvaptan 
concentrations was modified to estimate tolvaptan concentrations 
in subjects 44 weeks of gestational age to < 2 years of age and 
then 2 to < 4 years of age. It was estimated that doses of 0.1 
mg/kg and 0.15 mg/kg, respectively, would produce peak 
tolvaptan concentrations similar to those produced by a 15 mg 
tablet in an adult subject.  However, overall exposure as 
determined by AUC would be 33% and 13% lower, respectively, 
for < 2 years of age and 2 to < 4 years of age when compared to 
a 15 mg tablet in an adult.  It is expected that a 0.15 mg/kg starting 
dose of tolvaptan suspension would also be suitable for children 
> 4 years of age, as CYP3A expression would be the same as for 
children ≥ 2 to 4 years of age.  Suspension will only be dosed in 
children who weigh 30 kg or less to limit the amount of sorbitol 
administered; a 30 kg child titrated to a 0.6 mg/kg dose of 
tolvaptan as the suspension would receive approximately 9.6 g of 
sorbitol.


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or moderate CYP3A4 inhibitors.
Therefore, subjects < 2 years of age or < 10 kg will be 
administered tolvaptan as the suspension formulation with doses 
starting at 0.1 mg/kg.  Subjects 2 years of age, weighing 10 to 
< 20 kg and who can swallow a tablet will be administered an oral 
tablet once daily starting at a dose of 3.75-mg.  Subjects weighing 
20 to 50 kg, inclusive, and who can safely swallow a tablet, will 
receive an oral once daily dose of tolvaptan starting as a 7.5-mg 
spray-dried tablet.  Subjects ≥ 2 years of age, weighing ≤ 30 kg 
and who cannot safely swallow a tablet, will receive an oral, once 
daily dose of tolvaptan suspension staring at 0.15 mg/kg.  Subjects 
weighing > 50 kg will receive an oral once daily dose of tolvaptan 
starting as a 15-mg spray-dried tablet.
Tolvaptan is a sensitive CYP3A4 substrate; plasma concentrations 
increased approximately 4-fold when tolvaptan was administered 
with the potent CYP3A4 inhibitor ketoconazole.16,24 Where 
appropriate dose reductions are possible, tolvaptan doses may be 
coadministered with potent or moderate CYP3A4 inhibitors.  
Table 2.1.1-2  outlines starting dose 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.  As the smallest volume of suspension that can be 
administered is 0.3 mL (0.3kg), subjects weighing < 3 kg, < 6 kg 
and taking a moderate CYP3A4 inhibitor or weighing < 10kg and 
taking a potent CYP3A4 inhibitor may not be enrolled.


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New Text:  Table 2.1.1-2
Starting Tolvaptan Tablet Doses as mg/kg of Body Weight
Table 2.1.1-2 Starting Tolvaptan Tablet Doses in the Presence of Potent or 
Moderate CYP3A Inhibitors
Tolvaptan Dose
Age/Body Weight (as 
applicable)
Potent Inhibitor
Moderate Inhibitor
0.1 mg/kg 
suspensiona
44 wk to < 2 y or 
< 10 kg
-
0.05 mg/kg suspension
0.15 mg/kg 
suspension
2 y, ≤ 30 kg
0.04 mg/kg suspension
0.8 mg/kg suspension
3.75 mg tablet
10 kg to < 20 kg  
0.94 mL suspension
0.19 mL suspension
7.5 mg tablet
20 kg to 50 kg
1.90 mL suspension
3.75 mg tablet 
15 mg tablet
50 kg
3.75 mg tablet
7.5 mg tablet
aThe smallest volume of suspension that may be administered is 0.3 mL (0.3 mg), therefore dose reductions for potent inhibitors cannot be accommodated and 
for moderate inhibitors children weighing < 6 kg cannot be accommodated.


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3.1 Type of 
Trial:
This is the first clinical trial of tolvaptan in a pediatric 
population, and the majority of subjects may require only short-
term treatment of hyponatremia, however some subjects may 
require prolonged treatment and additional follow-up information 
on their response to tolvaptan may be desired to better understand 
its long-term safety profile in this pediatric population.  Hence, 
all subjects (responders and nonresponders) who complete this 
trial will be eligible for enrollment into an extension trial 
(156-11-294) to continue receiving tolvaptan, as clinically 
appropriate, until it is approved and available locally.  If eligible, 
subjects could continue therapy with tolvaptan in that trial after 
completing the 14 (+2) day Follow-up Visit and completion of 
this trial.  (The extension study will also provide long-term post-
treatment safety follow-up information for a minimum of 6 
months.)
The trial will be conducted in two stages. The first stage will be 
conducted using the available tablet formulation of tolvaptan 
whereas the second stage will expand to the use of a suspension 
once that formulation becomes available.
This is the first clinical trial of tolvaptan in a pediatric population, 
and the majority of subjects may require only short-term treatment 
of hyponatremia, however some subjects may require prolonged 
treatment and additional follow-up information on their response to 
tolvaptan may be desired to better understand its long-term safety 
profile in this pediatric population.  Hence, all subjects (responders 
and nonresponders) who participate in this trial will be eligible for 
enrollment into an extension trial (156-11-294) for a 6-month safety 
follow-up, regardless of treatment, and the option to continue 
receiving treatment with tolvaptan for hyponatremia based on 
clinical need. 
Figure 3.1-1 
Trial Design 
Schematic:
Schematic revised to reflect updated text in this section.
3.2.1 Tablet 
Formulation:
The maximum starting doses, by weight, for subjects are shown 
in Table 2.1.1-1 and are within the range previously used in trials 
involving adult hyponatremic subjects.
The palatability of tolvaptan tablets will be assessed.  
The maximum starting doses, by weight and age, for subjects are 
shown in Table 2.1.1-1 and are within the range previously used in 
trials involving adult hyponatremic subjects.
The palatability and acceptability of tolvaptan tablets will be 


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assessed.
The investigator has the option of performing a swallow test and 
providing coaching on swallowing techniques using placebo tablets 
if it is known or suspected that the subject is unable to swallow 
tablets.  Placebo tablets will be provided for use in performing this 
test at screening.
3.2.2 Suspension 
Formulation:
Additional information on the proposed suspension formulation 
of tolvaptan (currently in development) will be added to the 
protocol in an amendment when available. Until that time, 
subjects < 2 years of age or weighing < 10 kg and those unable to 
swallow tablets, are excluded from the trial.
Tolvaptan suspension, 1 mg/mL (0.1% w/v) will be administered 
orally once daily, preferably in the morning hours.  The treatment 
duration will be up to 5 days.  Any initiation or titration of 
tolvaptan must occur in a hospital setting. 
Subjects < 2 years of age or < 10 kg will be administered tolvaptan 
as the suspension formulation with doses starting at 0.1 mg/kg.  
Subjects 2 to < 4 years of age, weighing 10 to < 20 kg and who 
cannot swallow a tablet, can receive tolvaptan as the suspension 
formulation starting at 0.15 mg/kg.
The palatability and acceptability of tolvaptan suspension will be 
assessed.
3.2.3 Dosing 
Guidelines:
Subjects will be administered tolvaptan on an age- and weight-
based scale.  Titration of tolvaptan doses can occur once daily 
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.  Up-titration 
is limited to no more than twice the previous dose.
Subjects will be administered tolvaptan on a formulation, age- and 
weight-based scale.  Titration of tolvaptan doses can occur once 
daily 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.  
Up-titration is limited to no more than twice the previous dose.


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Subjects < 2 years of age or weighing < 10 kg are excluded until 
an oral suspension formulation is available.  
Subjects 2 years of age and weighing 10 to < 20 kg will 
receive a 3.75 mg tablet on Day 1 with possible up-titration to 7.5 
mg and 15 mg tablet doses.
Subjects weighing 20 to 50 kg, inclusive, will receive a 7.5 mg 
tablet on Day 1 with possible up-titration to 15 mg and 30 mg 
tablet doses.
Subjects weighing > 50 kg will receive a 15 mg tablet on Day 1 
with possible up-titration to 30 mg and 60 mg tablet doses.
...For subjects weighing 20 kg and taking moderate inhibitors 
of CYP3A4, one half of the standard 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.
Following their initial tolvaptan dose in the trial subjects will 
continue dosing according to the titration scheme (see 
Section 3.2.4), targeting a final serum sodium concentration 
between 135 and 140 mEq/L (mmol/L).  Titration guidelines are 
designed to achieve a change in serum sodium concentration of at 
least 4 to 8 mEq/L (mmol/L)/24 hours but not exceeding 
 
.
Subjects < 2 years of age, weighing < 10 kg will receive 0.1 mg/kg 
of the suspension on Day 1 with possible up-titration to 0.2 mg/kg 
and 0.4 mg/kg doses.
Subjects 2 years of age, weighing 10 to < 20 kg and who can 
safely swallow a tablet will receive a 3.75 mg tablet on Day 1 with 
possible up-titration to 7.5 mg and 15 mg tablet doses. 
Subjects weighing 20 to 50 kg, inclusive, and who can safely 
swallow a tablet, will receive a 7.5 mg tablet on Day 1 with 
possible up-titration to 15 mg and 30 mg doses.
Subjects 2 years of age, weighing ≤ 30 kg and who cannot safely 
swallow a tablet, can be given a 0.15 mg/kg dose of the suspension 
on Day 1 with possible up-titration to 0.3 mg/kg and 0.6 mg/kg 
doses.
Subjects weighing > 50 kg will be given a 15 mg tablet on Day 1
with possible up-titration to 30 mg and 60 mg doses.
...For subjects taking moderate inhibitors of CYP3A4, one half of 
the standard dose will be used.  For subjects taking potent inhibitors 
of CYP3A4, a one-quarter dose will be used.  The suspension 
formulation may be used in dose reductions for the tablet, see Table 
2.1.1-2.
Following their initial tolvaptan dose in the trial subjects will 
continue dosing according to the titration scheme (see 
Section 3.2.4), targeting a final serum sodium concentration 
between 135 and 140 mEq/L (mmol/L).  Titration guidelines are 
designed to achieve a change in serum sodium concentration of at 


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least 4 to 8 mEq/L (mmol/L)/24 hours but not exceeding 
 
.


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Old Text: 
Table 3.2.3-1 Dosing Schedule
Table 3.2.3-1 Dosing Schedule
Trial 
Day
Group
Time
Dose
Day 1
All subjects
Hour 0
3.75, 7.5, or 15 mg 
(as applicable)
Day 2
All subjects
24 (4) h post first dose
3.75, 7.5, 15, or 30 mg 
(as applicable)
Day 2a
(optional)
24 (4) h post previous dose
3.75, 7.5, 15, 30 or 60 mg 
(as applicable)
Day 3
Late Withdrawal 
and 
Nonresponders 
continuing on 
tolvaptan
24 (4) h post previous dose
3.75, 7.5, 15, 30, or 60 mg 
(as applicable)
Day 4
Late Withdrawal 
and 
Nonresponders 
continuing on 
tolvaptan
24 (4) h post previous dose
3.75, 7.5, 15, 30, or 60 mg 
(as applicable)


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New Text: 
Table 3.2.3-1 Dosing Schedule
Table 3.2.3-1 Dosing Schedule
Trial 
Day
Group
Time
Dose
Day 1
All subjects
Hour 0
0.1 or 0.15 mg/kg suspension
3.75, 7.5, or 15 mg tablets
(as applicable)
Day 2
All subjects
24 (4) h post first dose
0.1, 0.15, 0.2, or 0.3 mg/kg  
suspension
3.75, 7.5, 15, or 30 mg 
(as applicable)
Day 2a
(optional)
24 (4) h post previous dose
0.1, 0.15, 0.2, 0.3, 0.4, or 0.6 mg/kg 
suspension
3.75, 7.5, 15, 30 or 60 mg 
(as applicable)
Day 3
Late Withdrawal 
and 
Nonresponders 
continuing on 
tolvaptan
24 (4) h post previous dose
0.1, 0.15, 0.2, 0.3, 0.4, or 0.6  mg/kg 
suspension3.75, 7.5, 15, 30, or 60 
mg 
(as applicable)
Day 4
Late Withdrawal 
and 
Nonresponders 
continuing on 
tolvaptan
24 (4) h post previous dose
0.1, 0.15, 0.2, 0.3, 0.4, or 0.6  mg/kg 
suspension
3.75, 7.5, 15, 30, or 60 mg 
(as applicable)


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Figure 3.2.4-1 
Titration and 
Rescue Therapy 
Scheme:
Schematic revised to reflect updated text in this section.
3.2.4.2 Rescue 
Therapy:
...If at any point during the trial serum sodium levels or 
hyponatremia symptoms worsen or fail to improve adequately 
and definitive therapy (eg, isotonic or hypertonic saline) is 
required, the subject will be withdrawn from trial treatment to 
receive rescue therapy.  
Additional guidelines for rescue therapy concerning 
hyponatremia symptoms and decreasing serum sodium level:

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.
Subjects who are randomized to the Early Withdrawal group will 
initially be observed to determine whether additional intervention 
is required to maintain appropriate serum sodium levels.  Those 
subjects whose serum sodium declines by 4 mEq/L (mmol/L) 
or whose overall clinical condition requires further treatment to 
increase serum sodium will be treated per standard of care.  Any 
...If at any point during the trial serum sodium levels or 
hyponatremia symptoms worsen or fail to improve adequately and 
definitive therapy (eg, isotonic or hypertonic saline) is required, the 
subject will be withdrawn from trial treatment to receive rescue 
therapy Please see Section 4.2 for further details.  
Additional guidelines for rescue therapy concerning hyponatremia 
symptoms and decreasing serum sodium level:

If a subject has worsening symptoms and/or has a serum 
sodium lev
t 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 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.
Subjects who are randomized to the Early Withdrawal group will 
initially be observed to determine whether additional intervention is 
required to maintain appropriate serum sodium levels.  For those 
subjects whose serum sodium declines by 4 mEq/L (mmol/L) or 
whose overall clinical condition requires further treatment to 


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intervention intended to raise serum sodium level during the first 
48 hours in the responder Early Withdrawal group (including 
fluid restriction) will be defined as rescue therapy.  These
subjects will be considered to have reached their clinical 
endpoint, and their data will be censored from that time forward.
increase serum sodium, the investigator may consider rescue 
therapy per local standard of care.  Any intervention intended to 
raise serum sodium level during the first 48 hours in the responder 
Early Withdrawal group (including fluid restriction) will be defined 
as rescue therapy.  These subjects will be considered to have 
reached their clinical endpoint, and their data will be censored from 
that time forward.
3.3 Trial 
Population:
This trial will include up to 100 male and female subjects aged 
4 weeks (or 44 weeks adjusted gestational age) to < 18 years 
who have been diagnosed with euvolemic or hypervolemic 
hyponatremia (< 130 mEq/L [mmol/L]) that persists despite 
initial standard background therapy (including fluid restriction 
and excluding a vasopressin antagonist). Age groups will be 
enrolled such that 50% of these subjects will be < 10 years old 
and at least 25% of subjects < 6 years old.  Subjects who are 
defined as responders will be further stratified by the magnitude 
of serum sodium response to tolvaptan (7 and > 7 mEq/L 
[mmol/L]), and underlying etiology of hyponatremia.
Subjects with euvolemic or hypervolemic hyponatremia eligible 
to be screened for participation in this trial include, but are not 
limited to, those diagnosed and admitted to a hospital for 
treatment of HF, hepatocellular disease (including cirrhosis), or 
SIADH/other.  Subjects with acute hyponatremia or 
hyponatremia expected to resolve spontaneously will be excluded 
from the trial.  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 
This trial will include approximately 100 male and female subjects 
aged 4 weeks (or 44 weeks adjusted gestational age) to < 18 
years who have been diagnosed with euvolemic or hypervolemic 
hyponatremia (< 130 mEq/L [mmol/L]) that persists despite initial 
standard background therapy (including fluid restriction and 
excluding a vasopressin antagonist).  Age groups will be enrolled 
such that at least 50% of these subjects will be < 10 years old and at 
least 25% of subjects < 6 years old.  Subjects who are defined as 
responders will be further stratified by the magnitude of serum 
sodium response to tolvaptan (7 and > 7 mEq/L [mmol/L]), age, 
and underlying etiology of hyponatremia.
Subjects with euvolemic or hypervolemic hyponatremia eligible to 
be screened for participation in this trial include, but are not limited 
to, those diagnosed and admitted to a hospital for treatment of HF, 
hepatocellular disease (including cirrhosis), or SIADH/other.  
Subjects with acute hyponatremia or hyponatremia expected to 
resolve spontaneously will be excluded from the trial.  Children 
with an impaired ability to sense or communicate their thirst will 
either be required to undergo closer in-hospital observation, 
laboratory and urine output monitoring, or will be excluded from


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output monitoring, or will be excluded from the trial 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 excluded from this trial. 
All potential subjects must have chronic (48 hours) dilutional 
hyponatremia (euvolemic or hypervolemic) associated with HF, 
hepatocellular disease (including cirrhosis), or SIADH/other and 
be deemed by the investigator as likely to benefit from a therapy 
that raises serum sodium levels. The etiology of hyponatremia 
(presumed cause) must be documented and evaluated per 
Section 3.3.1.  Those subjects 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 are excluded from this trial. 
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 this protocol, persistent hyponatremia will be defined 
as serum sodium level < 130 mEq/L (mmol/L) documented as 
present for at least 48 hours.  Specifically, subjects must have 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 as 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 
the trial 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 excluded 
from this trial. 
All potential subjects must have chronic (48 hours) dilutional 
hyponatremia (euvolemic or hypervolemic) associated with HF, 
hepatocellular disease (including cirrhosis), or SIADH/other and be 
deemed by the investigator as likely to benefit from a therapy that 
raises serum sodium levels.  The etiology of hyponatremia 
(presumed cause) must be documented and evaluated per 
Section 3.3.1.  Those subjects 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 are 
excluded from this trial. 
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 this protocol, 
persistent hyponatremia will be defined as serum sodium level 
< 130 mEq/L (mmol/L) documented as present for at least 48 
hours.  Specifically, subjects must have 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 as per standard of care.  A third  (STAT) serum sodium 
assessment < 130 mEq/L (mmol/L), which will serve as the 
baseline value for final trial qualification and clinical management 


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New Text
be obtained within 2-4 hours prior to the first dose of trial 
medication.
strategy, is to be obtained within 2-4 hours prior to the first dose of 
trial medication.  This assessment will also serve as the baseline 
value for secondary and exploratory endpoints.
3.4 Eligibility 
Criteria:
Eligible subjects must satisfy all informed consent requirements, 
as well as meet all inclusion and exclusion criteria.  Subjects who 
do not meet all of these requirements are to be defined as screen 
failures and may rescreen, if eligible, at a later date.
Eligible subjects must satisfy all informed consent and assent 
requirements, as well as meet all inclusion and exclusion criteria.  
Subjects who do not meet all of these requirements are to be 
defined as screen failures and may rescreen, if eligible, at a later 
date.
3.4.1 Informed 
Consent/Assent:
3.4.1  Informed Consent
Written informed consent 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 Screening and as such must be able to 
understand that he or she can withdraw from the trial at any time.
3.4.1  Informed Consent/Assent
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 Screening and as such must be able to 
understand that he or she can withdraw from the trial at any time.
...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.


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Old Text: 
Table 3.4.2-1 Inclusion Criteria
Subjects are required to meet the following inclusion criteria:
Table 3.4.2-1 Inclusion Criteria
1.
Male and female subjects 4 weeks (or 44 weeks adjusted gestational age for premature births) to < 18 years old
2.
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
3.
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 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 2-4 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 Screening 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 IMP for 
sexually active females of childbearing potential
IMP = investigational medicinal product.


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New Text: 
Table 3.4.2-1 Inclusion Criteria
Subjects are required to meet the following inclusion criteria:
Table 3.4.2-1 Inclusion Criteria
1.
Male and female subjects 4 weeks (or 44 weeks adjusted gestational age for premature births) to < 18 years old
2.
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
3.
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 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 final 
trial qualification and clinical management strategy, is to be obtained within 2-4 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 Screening 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 IMP 
for sexually active females of childbearing potential
IMP = investigational medicinal product.


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Old Text: 
Table 3.4.3-1 Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria prior to trial entry.
Table 3.4.3-1 Exclusion Criteria
3.
Use of potent CYP3A4 inhibitors in subjects 50 kg or moderate CYP3A4 inhibitors in subjects < 20 kg
25.
Subjects <2 years of age, weight <10 kg, or who cannot swallow an oral tablet are excluded until an oral suspension formulation becomes available
New Text: 
Table 3.4.3-1 Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria prior to trial entry.
Table 3.4.3-1 Exclusion Criteria
3.
Current use or expected use during the trial of a potent CYP3A4 inhibitor in subjects weighing < 10 kg or a moderate CYP3A4 inhibitor in subjects
weighing < 6 kg
25.
Subjects who weigh < 3 kg
26.
Unable to swallow tablets if the suspension formulation is unavailable
Use of the suspension formulation is at the discretion of the local regulatory authorities and IRB/IECs.  In such cases, subjects who 
require use of suspension for either standard dosing or adjusted dosing (eg, concomitant use of CYP3A4 inhibitors) cannot be 
enrolled.


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3.7 Trial 
Procedures:
In Treatment Phase A, subjects who meet the inclusion and 
exclusion criteria will be enrolled and will be administered a 
3.75-, 7.5-, or 15-mg dose tablet based on age, weight, and the 
use of CYP3A4 inhibitors.  At the end of Day 2 (or 2a) in 
Treatment Phase A, subjects who are responders will be 
randomized to either continue treatment with tolvaptan for 
2 additional days (Late Withdrawal) or to discontinue tolvaptan 
treatment (Early Withdrawal).
In Treatment Phase B, subjects who are nonresponders may 
continue on tolvaptan therapy for 2 additional days or may be 
withdrawn from tolvaptan to be treated per the investigator’s 
preferred standard of care.  During Treatment Phase B, subjects 
in the Late Withdrawal group and nonresponders continuing 
treatment will continue to receive tolvaptan for 2 additional days 
and all subjects will have serum sodium levels measured at 12 (
4) hours post-dose and at trough each day.  Subjects in the Early 
Withdrawal group should be monitored for the first 48 hours 
post-last dose.
In Treatment Phase A, subjects who meet the inclusion and 
exclusion criteria will be enrolled and will be administered 
tolvaptan doses based on age, weight, ability to swallow a tablet,  
and the use of CYP3A4 inhibitors.  At the end of Day 2 (or 2a) in 
Treatment Phase A, subjects who are responders will be 
randomized to either continue treatment with tolvaptan for 
2 additional days (Late Withdrawal) or to discontinue tolvaptan 
treatment (Early Withdrawal).
In Treatment Phase B, subjects who are nonresponders may 
continue on tolvaptan therapy for 2 additional days or may be 
withdrawn from tolvaptan to be treated per the investigator’s 
preferred standard of care.  During Treatment Phase B, subjects in 
the Late Withdrawal group and nonresponders continuing treatment 
will continue to receive tolvaptan for 2 additional days and all 
subjects will have serum sodium levels measured at 12 (4) hours 
postdose and at trough each day.  Subjects in the Early Withdrawal 
group should be monitored for the first 48 hours post-last dose.


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Old Text:  Table 3.7-1
Schedule of Assessments
Table 3.7-1
Schedule of Assessments
Procedures
Screening
Treatment Phase A
Treatment Phase B
Follow-up Phase C
Day -2 
and -1
Day 1
Day 2
Day 2a 
(optional)
Day 3
Day 4
Day 5
72 (4) h 
post last 
dose
7 (1) 
days post-
last dose
14 (+2) 
days post-
last dose
Early 
Termin-
ation (ET)
Informed Consent/Assent
X
Inclusion/exclusion 
criteriaa
X
X
Demographic information
X
Medical and 
hyponatremia history
X
Vital signsb
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
Height
X
Body weightc
X
X
X
X
X
X
X
X
X
X
Directed physical 
examination
X
X
X
X
X
X
X
X
X
Tanner staging
X
Neurological examination
X
X
X
X
X
X
X
X
Neurocognitive 
assessmentd
X
X
X
X
X
X
X
X
X
X
Quality of life assessment
X
X
X
Clinical status 
assessmente
X
X
X
X
X
X
X
X
X
Alcohol/drug screen
X
Pregnancy test (if 
applicable)f
X
Fluid intakeg
X
X
Urine volumeg
X
X


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Table 3.7-1
Schedule of Assessments
Procedures
Screening
Treatment Phase A
Treatment Phase B
Follow-up Phase C
Day -2 
and -1
Day 1
Day 2
Day 2a 
(optional)
Day 3
Day 4
Day 5
72 (4) h 
post last 
dose
7 (1) 
days post-
last dose
14 (+2) 
days post-
last dose
Early 
Termin-
ation (ET)
Urinalysis
X
X
X
Urine chemistryg,h
X
X
X
Serum sodiumi
X
X
X
X
X
X
X
X
X
X
Hematology, coagulation, 
and serum chemistryj
X
X
X
Serum osmolality, FENa, 
and FE urate
X
TSH and cortisolk
X
PK plasma samplesl
X
X
X
X
X
X
Tolvaptan dosingm
X
X
X
X
X
Assessment for response 
to tolvaptan
X
X
Palatability assessment
X
Randomization
X
Follow-up phone call or 
visit
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; TSH = thyroid-stimulating hormone.
aInclusion/exclusion criteria will be checked at screening and predose on Day 1.
bVital signs to be assessed include supine blood pressure, heart rate, respiratory rate, and temperature.  Vital signs should be assessed prior to any blood 
draws.
cWeight will be taken predose as possible.
dNeurocognitive assessments are closely tied to serum sodium assessments and should be done within 1 hour of sodium blood draws.


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eClinical status assessments will be performed per inpatient standard of care, ie, review patient chart entries (including hyponatremia assessment notes and 
laboratory results [trial and nontrial specific], any examination findings, medical problem list changes, and fluid intake and output) to evaluate overall 
subject eligibility in terms of hyponatremia state.
fUrine pregnancy tests will be performed on female subjects 12 years of age and all female subjects < 12 years of age if menstruation has started.
gIntervals starting immediately after dosing at Hour 0 (0-6, 6-12, 12-18, and 18-24 hours).
hSamples within a collection interval are to be refrigerated and pooled.  An aliquot for urine chemistry tests will be taken for each collection interval.  Uric 
acid is to be measured at screening only.
iSerum sodium assessments are closely tied to neurocognitive assessments, dosing time points and PK blood draws.

Screening: 2 assessments should be taken, at least 12 hours apart (may be part of medical history). 1 assessment can be combined with the serum 
chemistry panel.

Treatment Phase A: Baseline [STAT] assessment will be at 2-4 hours prior to first dose. Post-first dose assessments: 8 and 24 (trough) hours. Then 
every 12 hours thereafter (alternating 12 hours post-dose and at trough)

Treatment Phase B: Assessments to be taken every 12 hours (alternating 12 hours post-dose and at trough) 

Treatment Phase C: Assessments to be taken at 72 (± 4) hours post-last dose (can be combined with the serum chemistry panel) and at the 7 day 
post-last dose visit.
jSerum chemisty panel includes serum sodium and assessments can be combined for visits where both assessments are indicated.
kResults of these tests will further characterize hyponatremia etiology for the Hyponatremia History CRF and are not required to determine eligibility.  
Subjects who have clinically relevant TSH or cortisol levels may not respond properly to tolvaptan and will be withdrawn from the trial.
lPK samples are closely tied to dosing time points and serum sodium assessments. An ET sample will be collected only if ET is before the last scheduled PK 
assessment.

In Treatment Phase A PK samples should be collected at 2 and 8 hours and at trough post-first dose.

In Treatment Phase B PK will be assessed in subjects continuing treatment with tolvaptan (Late Withdrawal group and nonresponders continuing on 
tolvaptan) at trough on Days 3, 4 and 5.
mThe tolvaptan dose will be titrated based on serum sodium levels as described in Section 3.2.4.


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NewText:  Table 3.7-1
Schedule of Assessments
Table 3.7-1
Schedule of Assessments
Procedures
Screening
Treatment Phase A
Treatment Phase B
Follow-up Phase C
Day -2 
and -1
Day 1
Day 2
Day 2a 
(optional)
Day 3
Day 4
Day 5
72 (4) h 
post last 
dose
7 (1) 
days post-
last dose
14 (+2) 
days post-
last dose
Early 
Termin-
ation (ET)
Informed Consent/Assent
X
Inclusion/exclusion 
criteriaa
X
X
Demographic information
X
Medical and 
hyponatremia history
X
Vital signsb
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
Height
X
Body weightc
X
X
X
X
X
X
X
X
X
X
Physical examination
Xd
X
X
X
X
X
X
X
X
Tanner staging
X
Neurological examination
X
X
X
X
X
X
X
X
Neurocognitive 
assessmente
X
X
X
X
X
X
X
X
X
X
Quality of life assessment
X
X
X
Clinical status assessmentf
X
X
X
X
X
X
X
X
X
Alcohol/drug screen
X
Pregnancy test (if 
applicable)g
X
X
Fluid intakeh
X
X
Urine volumeh
X
X
Urinalysis
X
X
X


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Table 3.7-1
Schedule of Assessments
Procedures
Screening
Treatment Phase A
Treatment Phase B
Follow-up Phase C
Day -2 
and -1
Day 1
Day 2
Day 2a 
(optional)
Day 3
Day 4
Day 5
72 (4) h 
post last 
dose
7 (1) 
days post-
last dose
14 (+2) 
days post-
last dose
Early 
Termin-
ation (ET)
Urine chemistryh,i
X
X
X
Serum sodiumj
X
X
X
X
X
X
X
X
X
X
Hematology, coagulation, 
and serum chemistryk
X
X
X
Serum osmolality, FENa, 
and FE urate
X
TSH and cortisoll
X
PK plasma samplesm
X
X
X
X
X
X
Tolvaptan dosingn
X
X
X
X
X
Swallow test
Xo
Assessment for response 
to tolvaptan
X
X
Palatability and 
acceptability assessment
X
Randomization
X
Follow-up phone call or 
visit
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; TSH = thyroid-stimulating hormone.
aInclusion/exclusion criteria will be checked at screening and predose on Day 1.
bVital signs to be assessed include supine blood pressure, heart rate, respiratory rate, and temperature.  Vital signs should be assessed prior to any blood 
draws.
cWeight will be taken predose as possible.


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dThe initial physical examination should be a full physical.  Subsequent physical examinations can be directed physical examinations that are focused on 
hyponatremia-related signs and symptoms as well as any major changes from baseline.
eNeurocognitive assessments are closely tied to serum sodium assessments and should be done within 1 hour of sodium blood draws.
fClinical status assessments will be performed per inpatient standard of care, ie, review patient chart entries (including hyponatremia assessment notes and 
laboratory results [trial and nontrial specific], any examination findings, medical problem list changes, and fluid intake and output) to evaluate overall subject 
eligibility in terms of hyponatremia state.  Volume status will be assessed every 6 hours prior to trial entry and every 6 hours during Treatment Phase A.
gPregnancy tests will be performed on female subjects 12 years of age and all female subjects < 12 years of age if menstruation has started.
hIntervals starting immediately after dosing at Hour 0 (0-6, 6-12, 12-18, and 18-24 hours).
iSamples within a collection interval are to be refrigerated and pooled.  An aliquot for urine chemistry tests will be taken for each collection interval.  Uric 
acid is to be measured at screening only.
jSerum sodium assessments are closely tied to neurocognitive assessments, dosing time points and PK blood draws.

Screening: 2 assessments should be taken, at least 12 hours apart (may be part of medical history).  One assessment can be combined with the 
serum chemistry panel.

Treatment Phase A: Baseline [STAT] assessment will be at 2-4 hours prior to first dose.  Post-first dose assessments: 8 and 24 (trough) hours.  Then 
every 12 hours thereafter (alternating 12 hours postdose and at trough)

Treatment Phase B: Assessments to be taken every 12 hours (alternating 12 hours postdose and at trough)

Treatment Phase C: Assessments to be taken at 72 (± 4) hours post-last dose (can be combined with the serum chemistry panel) and at the 7 day 
post-last dose visit.
In addition to serum sodium samples obtained for trial 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, and on Day 2 (and Day 
2a, if applicable) at 6 hours postdose as well as at 18 hours postdose.  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).
kSerum chemisty panel includes serum sodium and assessments can be combined for visits where both assessments are indicated.
lResults of these tests will further characterize hyponatremia etiology for the Hyponatremia History CRF and are not required to determine eligibility.  
Subjects who have clinically relevant TSH or cortisol levels may not respond properly to tolvaptan and will be withdrawn from the trial.
mPK samples are closely tied to dosing time points and serum sodium assessments.  An ET sample will be collected only if ET is before the last scheduled PK 
assessment.

In Treatment Phase A PK samples should be collected at 2 and 8 hours and at trough post-first dose.

In Treatment Phase B PK will be assessed in subjects continuing treatment with tolvaptan (Late Withdrawal group and nonresponders continuing on 
tolvaptan) at trough (24 hours post last dose, immediately  prior to next dose) on Days 3, 4 and 5.


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nThe tolvaptan dose will be titrated based on serum sodium levels as described in Section 3.2.4.
oOptional swallow test for subjects who are known or suspected to be unable to swallow tablets, at the investigator’s discretion.
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Updated Text
3.7.1.1 
Screening:
A directed physical examination will be performed.
Tanner staging will be performed.
A neurocognitive assessment will be performed, as appropriate 
by age and where available.
Quality-of-life (QoL) assessment will be performed, as 
appropriate by age and where available.
Clinical status assessments will be performed per inpatient 
standard of care.
Alcohol and drug screens will be performed, as age appropriate.
A urine pregnancy test will be performed on all female subjects 
12 years of age and all female subjects < 12 years of age if 
menstruation has started. 
Urinalysis and urine chemistry laboratory samples will be 
collected for analysis. 
Two blood samples for serum sodium testing will be collected at 
least 12 hours apart and can be part of the recent medical history 
to document chronic hyponatremia.  (One of these blood draws 
can be combined with the serum chemistry panel as appropriate 
to minimize blood draws.)
Hematology, coagulation, and serum chemistry laboratory 
samples will be collected for analysis.
A full physical examination will be performed.  The initial physical 
examination should be a full physical.  Subsequent physical 
examinations can be directed physical examinations that are 
focused on hyponatremia-related signs and symptoms as well as 
any major changes from baseline.
Tanner staging will be performed.
A neurocognitive assessment will be performed, as appropriate by 
age and where available and should be done within 1 hour of serum 
sodium blood draw.
Quality-of-life (QoL) assessment will be performed, as appropriate 
by age and where available.
Clinical status assessments will be performed per inpatient standard 
of care.
Alcohol and drug screens will be performed, as age appropriate.
A pregnancy test will be performed on all female subjects 
12 years of age and all female subjects < 12 years of age if 
menstruation has started. 
Urinalysis and urine chemistry laboratory samples will be collected 
for analysis. 
Two blood samples for serum sodium testing will be collected at 
least 12 hours apart and can be part of the recent medical history to 
document chronic hyponatremia.  (One of these blood draws can be 


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Updated Text
Serum osmolality, FENa, and FE urate will be determined.
Thyroid-stimulating hormone (TSH) and cortisol blood samples 
will be collected to determine possible need for alternate mode of 
therapy.
Concomitant medications will be recorded.
Adverse events will be recorded.
combined with the serum chemistry panel as appropriate to 
minimize blood draws.)
Hematology, coagulation, and serum chemistry laboratory samples 
will be collected for analysis.
Serum osmolality, FENa, and FE urate will be determined.
Thyroid-stimulating hormone (TSH) and cortisol blood samples 
will be collected to determine possible need for alternate mode of 
therapy.
Concomitant medications will be recorded.
Adverse events will be recorded.
Optional swallow test for subjects who are known or suspected to 
be unable to swallow tablets, at the investigator’s discretion.  
Placebo tablets will be provided for use in performing this test at 
screening.
3.7.1.2.1 Day 1:
16)  A neurological examination will be performed at 8 hours 
post-first dose.
A neurological examination will be performed at 8 hours post-first 
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 


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Updated Text
they can be combined with standard of care labs).
3.7.1.2.2 Day 2:
Postdose
Assess palatability of tolvaptan tablets for subjects.
Fluid intake will be recorded at 6-hour intervals starting at 
Hour 0 (0-6, 6-12, 12-18, and 18-24 hours).
Urine will be collected at 6-hour intervals starting at Hour 0 (0-6, 
6-12, 12-18, and 18-24 hours). Subjects should be asked to void 
just prior to the end time of each collection interval, as possible. 
Urine volume will be determined from urine voids made during 
the 6-hour collection intervals which will be pooled prior to 
determination of final volume.
A urine chemistry sample will be collected and assessed from 
each 6-hour volume interval starting at Hour 0 (0-6, 6-12, 12-18, 
and 18-24 hours).
Clinical status assessments will be performed per inpatient 
standard of care, ie, patient chart entries will be reviewed 
(including hyponatremia assessment notes, including laboratory 
results [trial and nontrial specific], any examination findings, 
medical problem list changes, and fluid intake and output) to 
evaluate the subject’s hyponatremia state.
A blood sample will be collected for serum sodium testing at 
12 hours post-dose.
Postdose
Assess palatability and acceptability of tolvaptan dose for subjects.
Fluid intake will be recorded at 6-hour intervals starting at Hour 0 
(0-6, 6-12, 12-18, and 18-24 hours).
Urine will be collected at 6-hour intervals starting at Hour 0 (0-6, 6-
12, 12-18, and 18-24 hours).  Subjects should be asked to void just 
prior to the end time of each collection interval, as possible. 
Urine volume will be determined from urine voids made during the 
6-hour collection intervals which will be pooled prior to 
determination of final volume.
A urine chemistry sample will be collected and assessed from each 
6-hour volume interval starting at Hour 0 (0-6, 6-12, 12-18, and 18-
24 hours).
Clinical status assessments will be performed per inpatient standard 
of care, ie, patient chart entries will be reviewed (including 
hyponatremia assessment notes, including laboratory results [trial 
and nontrial specific], any examination findings, medical problem 
list changes, and fluid intake and output) to evaluate the subject’s 
hyponatremia state.
A blood sample will be collected for serum sodium testing at 
12 hours postdose.
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 


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of care sodium assessment unit, where available, at 6 and 18 hours 
postdose.  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).
3.7.1.2.3 Day 2a 
(optional):
Postdose
7)
Clinical status assessments will be performed per 
inpatient standard of care, ie, patient chart entries will be 
reviewed (including hyponatremia assessment notes, 
including laboratory results [trial and nontrial specific], 
any examination findings, medical problem list changes, 
and fluid intake and output) to evaluate the subject’s 
hyponatremia state.
8)
A blood sample will be collected for serum sodium 
testing at 12 hours postdose.
Postdose
Clinical status assessments will be performed per inpatient standard 
of care, ie, patient chart entries will be reviewed (including 
hyponatremia assessment notes, including laboratory results [trial 
and nontrial specific], any examination findings, medical problem 
list changes, and fluid intake and output) to evaluate the subject’s 
hyponatremia state.
A blood sample will be collected for serum sodium testing at 
12 hours postdose.
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.  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).
3.7.1.4.2 7 Days 
Post-last Dose:
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 
performed prior to blood draws.
2)
A blood sample for serum sodium testing will be 
collected.
11) 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 blood draws.
12) A blood sample for serum sodium testing will be collected.
13) A pregnancy test will be performed on all female subjects 


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3)
A neurocognitive assessment will be performed within 1 
hour of the serum sodium sample.
12 years of age and all female subjects < 12 years of age 
if menstruation has started. 
14) A neurocognitive assessment will be performed within 1 
hour of the serum sodium sample.
3.7.2.1 Serum 
Sodium 
Concentrations:
Monitoring frequency of serum sodium is at the discretion of the 
clinical investigator; however, the minimum sample collection 
required for all subjects is described in Section 3.7.1.
In order to qualify for this trial, subjects must have 
documentation of chronic dilutional hyponatremia (serum sodium 
< 130 mEq/L [mmol/L]) that is present for ≥48 hours.  
Specifically, each subject must have 2 blood samples collected at 
least 12 hours apart over a minimum of 48 hours for assessment 
of baseline serum sodium level to determine subject eligibility.  
These can be either part of the recent medical history concerning 
the current hospital stay or prospectively collected as part of this 
trial.
On Day 1, a third (STAT) serum sodium sample should be drawn 
within 2-4 hours prior to dosing; the results must be verified to be 
< 130 mmol/L prior to the first dose.  Serum sodium assessments 
should be performed at 8 hours post-first dose and at trough 24 
hours post-first dose (this assessment will fall on Day 2 predose). 
On Day 2 (or 2a), Day 3, and Day 4 (through the following 
morning on Day 5):
For all subjects receiving tolvaptan (Late Withdrawal and 
Nonresponders continuing on tolvaptan) serum sodium 
assessments will be performed at trough and 12 hours post-dose 
each day during Treatment Phase A and Treatment Phase B.
Monitoring frequency of serum sodium is at the discretion of the 
clinical investigator; however, the minimum sample collection 
required for all subjects is described in Section 3.7.1 and Section 
3.7.4.2.1.
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).
In order to qualify for this trial, subjects must have documentation 
of chronic dilutional hyponatremia (serum sodium < 130 mEq/L 
[mmol/L]) that is present for ≥48 hours.  Specifically, each subject 
must have 2 blood samples collected at least 12 hours apart over a 
minimum of 48 hours for assessment of baseline serum sodium 
level to determine subject eligibility.  These can be either part of 
the recent medical history concerning the current hospital stay or 
prospectively collected as part of this trial.
On Day 1, a third (STAT) serum sodium sample should be drawn 
within 2-4 hours prior to dosing; the results must be verified to be 
< 130 mmol/L prior to the first dose.  Serum sodium assessments 


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For all subjects not receiving tolvaptan (Early Withdrawal and 
Nonresponders on standard of care) serum sodium assessments 
will be performed every 12 hours throughout Treatment Phase A 
and Treatment Phase B.  
For all subjects final serum sodium assessments will be taken at 
24 (± 4) and 72 (± 4) hours post-last dose as well as at 7 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.
should be performed at 8 hours post-first dose and at trough 24
hours post-first dose (this assessment will fall on Day 2 predose). 
On Day 2 (or 2a), Day 3, and Day 4 (through the following 
morning on Day 5):

For all subjects receiving tolvaptan (Late Withdrawal 
and Nonresponders continuing on tolvaptan) serum 
sodium assessments will be performed at trough and 
12 hours postdose each day during Treatment Phase A 
and Treatment Phase B.

For all subjects not receiving tolvaptan (Early 
Withdrawal and Nonresponders on standard of care) 
serum sodium assessments will be performed every 12 
hours throughout Treatment Phase A and Treatment 
Phase B.  
For all subjects final serum sodium assessments will be taken at 24 
(± 4) and 72 (± 4) hours post-last dose as well as at 7 days post-last 
dose.
3.7.3.1.1 Blood 
Collection 
Times:
Blood samples will be taken so that tolvaptan and metabolite 
concentrations can be determined. Samples will be taken on Day 
1 at 2 hours (5 minutes) and 8 hours (concurrent with 8 h serum 
sodium sample) post-first dose.  On Days 2, 3, 4 and 5 samples 
will be taken at trough (24 hours post previous dose but prior to 
the subsequent dose), concurrent with serum sodium samples,  
for subjects dosed with tolvaptan on Days 1, 2, 3, and/or 4, 
respectively, regardless of status as responder/non-responder.  An 
early termination (ET) sample will be taken if ET occurs prior to 
the last planned PK sample. No ET sample is required if ET 
Blood samples will be taken so that tolvaptan and metabolite 
concentrations can be determined.  Samples will be taken at the 
following times:
On Day 1 at 2 hours (5 minutes) and 8 hours (concurrent with 8 h 
serum sodium sample) post-first dose.  
On Days 2, 3, 4 and 5 samples will be taken at trough (prior to the 
subsequent dose), concurrent with serum sodium samples,  for 
subjects dosed with tolvaptan on Days 1, 2, 3, and/or 4, 
respectively, regardless of status as responder/non-responder.


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occurs at the same visit where a PK sample has already been 
obtained.
For each PK blood sample collected volumes are not expected to 
exceed 1.2 mL. Total volume per sample may be lower 
depending on finalization of blood collection supplies.  
Serum sodium assessments and other clinically necessary blood 
samples take priority, therefore, due to restrictions in allowable 
total daily blood volumes based on local guidelines and subject 
age, it may not be possible to take more than one PK sample per 
day. If so, the PK sampling should be changed to:
Day 1: 2 hours post dose (5 minutes)
Day 2: 8 (2) hours post dose (may be concurrent with serum 
sodium or other blood sampling)
Day 3 at trough, ie, pre-dose/24 hours post prior dose (concurrent 
with serum sodium sample)
An early termination (ET) sample will be taken if ET occurs prior 
to the last planned PK sample.  No ET sample is required if ET 
occurs at the same visit where a PK sample has already been 
obtained.
For each PK blood sample collected volumes are not expected to 
exceed 1.2 mL.  Total volume per sample may be lower depending 
on finalization of blood collection supplies.  
Serum sodium assessments and other clinically necessary blood 
samples take priority, therefore, due to restrictions in allowable 
total daily blood volumes based on local guidelines and subject age, 
it may not be possible to take more than one PK sample per day.  If 
so, the PK sampling should be changed to:
Day 1: 2 hours postdose (5 minutes)
Day 2: 8 (2) hours postdose (may be concurrent with serum 
sodium or other blood sampling)
Day 3 at trough, ie, predose/24 hours post prior dose (concurrent 
with serum sodium sample) 
3.7.3.2.4 
Palatability and 
Acceptability 
Assessment:
New section for this amendment
A questionnaire will be administered once to assess palatability to 
rate flavor/taste, smell, sweetnees, and overall liking of the study 
medication immediately after dosing.  Subjects will also be asked 
about the ease of swallowing the study medication.  Between 15 to 
20 minutes after dosing, subjects will be asked again about overall 
liking of the study medication.  This assessment will only be done 
in subjects aged 3 years to 18 years.
3.7.4 Safety 
Assessments:
The monitoring frequency of safety assessments is at the 
The monitoring frequency of safety assessments is at the discretion 


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discretion of the clinical investigator; however, the trial requires 
the minimum sample collection for all subjects noted in Section
3.7.1.
of the clinical investigator; however, the trial requires the minimum 
sample collection for all subjects noted in Section 3.7.1 and Section
3.7.4.2.1.
3.7.4.2.1 Serum 
Sodium:
New section for this amendment
In addition to serum sodium samples obtained for trial 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 Treatment Phase A.  A point of care assessment unit is 
preferred since it is expected to reduce overall daily blood volume 
needed for assessments (expected 0.5 mL for regular blood draws 
versus up to several drops for a point of care assessment, depending 
on the device used); however, regular blood draws may be used 
(especially if they can be combined with standard of care labs).
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 unscheduled 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.
3.7.4.2.3 Clinical 
Lab Tests:
Table 3.7.4.2-1 presents required clinical laboratory assessments 
(serum chemistry, hematology, coagulation, urinalysis, and urine 
chemistry).  All clinical laboratory tests will be performed by 
local laboratories.  Serum cortisol and TSH will be measured 
during screening using the remaining blood sample obtained for 
Table 3.7.4.2-1 presents required clinical laboratory assessments 
(serum chemistry, hematology, coagulation, urinalysis, and urine 
chemistry).  All clinical laboratory tests will be performed by local 
laboratories.  Serum cortisol and TSH will be measured during 
screening using the remaining blood sample obtained for serum 


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serum chemistry.  If these results are obtained as part of the 
standard of care for the subject, a trial-specific sample should be 
obtained and sent to the local laboratory for analysis per the 
schedule of assessments (Section 3.7.1).  Uric acid will be 
measured during screening for calculation of FENa and FE urate.
chemistry.  If these results are obtained as part of the standard of 
care for the subject, a trial-specific sample should be obtained and 
sent to the local laboratory for analysis per the schedule of 
assessments (Section 3.7.1).  Uric acid will be measured during 
screening for calculation of FENa and FE urate.
It is recognized that there may be limitations based on age and 
weight of children for the amount of blood that can be drawn at a 
single time point, per day, and the overall conduct of the trial.  
Wherever possible, it is encouraged to combine standard of care 
samples that would be taken regardless of trial participation with 
those samples required for the trial.
In case of limited blood or urine volume availability, the bolded 
assessments in Table 3.7.4.2.3-1 take priority.  Serum sodium and 
liver function tests are essential to the conduct of the trial.
Table 3.7.4.2.3-1 
Clinical 
Laboratory Tests 
to be Performed 
Locally:
Urobilinogen
Additional Test:
Urine pregnancy (if applicable)
Urobilinogen
Additional Test:
Serum or urine pregnancy test (if applicable)
3.7.4.3 Physical 
Examination:
Directed physical examinations will be performed and 
documented according to the schedule of assessments 
(Section 3.7.1).
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 
Directed physical examinations will be performed and documented 
according to the schedule of assessments (Section 3.7.1).  The 
initial physical examination should be a full physical.  Subsequent 
physical examinations can be directed physical examinations that 
are focused on hyponatremia-related signs and symptoms as well as 
any major changes from baseline.
The principal investigator or his/her appointed designee is primarily 


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possible, the same individual should perform all physical 
examinations for a given subject.  Any condition present at the 
post-treatment directed physical examination that was not present 
at Screening should be documented as an AE and followed to a 
satisfactory conclusion.
All 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.  Neurological examinations 
will be performed in an age-appropriate manner per 
Section 3.7.4.3.1.
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 for a given 
subject.  Any condition present at the post-treatment directed 
physical examination that was not present at Screening should be 
documented as an AE and followed to a satisfactory conclusion.
All 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.  Neurological examinations will 
be performed in an age-appropriate manner per Section 3.7.4.3.1.
3.7.4.8 Volume 
Status 
Assessment:
New section for this amendment
Volume status will be assessed every 6 hours prior to trial entry and 
every 6 hours during Treatment Phase A.
3.9 Screen 
Failures:
...Subjects who are deemed screen failures may be rescreened for 
possible participation at a later date if no randomization number 
has been assigned.  Subjects who receive a randomization 
number may not be rescreened regardless of whether they receive 
trial medication.
...Subjects who are deemed screen failures may be rescreened for 
possible participation if they have not taken a dose of IMP.
4.1 Prohibited 
Medications:
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, subjects weighing 
20 kg and taking moderate inhibitors of CYP3A4 will be 
administered half of their regular dose of tolvaptan.  For subjects 
weighing > 50 kg and taking potent CYP3A4 inhibitors, with the 
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.  Tolvaptan is a 
sensitive CYP3A4 substrate; plasma concentrations increased 
approximately 4-fold when tolvaptan was administered with the 
potent CYP3A4 inhibitor ketoconazole.16,24 Where appropriate 
dose reductions are possible, tolvaptan doses may be 


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exception of amiodarone, which was previously found to have no 
effect on tolvaptan, a one-quarter dose will be used (3.75 mg).  
Moderate and potent CYP3A4 inhibitors are not allowed for 
subjects weighing < 20 and 50 kg, respectively.16,24  A partial 
list of CYP3A4 inhibitors is provided in Table 4.1-1.
coadministered with potent or moderate CYP3A4 inhibitors (see 
Section 2.1.1 and Table 2.2.2-1).
A partial list of CYP3A4 inhibitors is provided in Table 4.1-1.
4.2 Other 
Restrictions:
The use of saline in this population should be closely monitored.  
The use of hypertonic saline (3%), including normal saline 
challenge) within 8 hours of the qualifying screening serum 
sodium laboratory assessment is prohibited.
The use of saline in this population should be closely monitored.  
The use of hypertonic saline (3%), including normal saline 
challenge within 8 hours of the qualifying screening serum sodium 
laboratory assessment 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.
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 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 
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 oopherectomy 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 sterile (ie, women who have had a bilateral 
oophorectomy and/or hysterectomy or who have been 


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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 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 
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, condom with spermicide, or sponge 
with spermicide.  The following 3 contraceptive methods are not 
allowed in this trial:  birth control pills, birth control depot 
injection, and birth control implant.  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 


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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 will be followed for a minimum of 6 months.
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 parent/guardian.
A urine and/or serum pregnancy test for human chorionic 
gonadotropin (hCG) will be performed at screening on all WOCBP 
and 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 


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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.
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.
7.1.1 Sample Size 
for Efficacy:
...Sample size re-estimation will be conducted when 90% of the 
subjects finish (complete or discontinue) the trial.
...Sample size re-estimation will be conducted when 90% of the 
subjects finish (complete or discontinue) the trial.  The trial must 
include no fewer than 60 subjects on IMP for the assessment of 
safety based on regulatory feedback.
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 in blister packs.  Each blister 
pack used in the dosing period will be labeled to clearly disclose 
the, 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 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 in blister packs or as 60 mL bottles 
containing 1 mg/mL (0.1% w/v) tolvaptan suspension.  Each blister 
pack and suspension bottle  used in the dosing period will be 
labeled to clearly disclose the 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.  Each site will 


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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 or 50 kg 
who are taking moderate or potent inhibitors of CYP3A4, 
respectively.  Once available, the protocol will be amended to 
include the details of this formulation and will include 
information on the packaging and labeling for that formulation
be supplied with bottle(s) containing placebo tablets to use for 
subject screening purposes.  Each placebo bottle will be labeled to 
clearly disclose the compound ID, trial number, instruction for use, 
route of administration, appropriate precautionary statement, and 
other information required by the local regulatory authorities.  For 
dosing suspension, syringes and bottle adaptors will be made 
available to the sites.
8.2 Storage:
The IMP will be stored at 25C (77F) or below, with excursions 
allowed from 15 to 30C (59 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.
The IMP blister packs will be stored at 25C (77F) or below, with 
excursions allowed from 15 to 30C (59 to 86F).  The IMP 
suspension bottles will be stored at 2 to 8C (35.6 to 46.4F) and 
protected from light.  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.
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 

Documentation of the informed consent process, including 
any revised consents;

Documentation of the investigator’s decision to enroll the 
subject into the trial, the review of all inclusion/exclusion 
criteria prior to IMP administration, and confirmation of 
the subject’s actual participation in the trial;


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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.
...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.

The date of the visit and the corresponding Visit or Day in 
the trial schedule;

General subject status remarks, including any significant
medical findings.  The severity, frequency, duration, 
action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also 
be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed;

The signature (or initials) and date of each clinician (or 
designee) who made an entry in the progress notes.
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 GCP29 
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 E629 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 IMP 
development is discontinued, the date of 
discontinuation); OR
...The investigator will be responsible to maintain adequate and 

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 regulatory 
authorities were notified of discontinuation); OR
...The investigator will be responsible to maintain adequate and 


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accurate electronic or hard copy source documents of all 
observations and data generated during this trial.  
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 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 telephone and written 
communications.
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.
10.2 Auditing:
The sponsor’s Quality Management Unit (or representative) may 
conduct trial site audits.  Audits will include, but are not be 
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 be limited 
to, IMP 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, ICH 
GCP Guideline (E6), international ethical principles derived from 
the Declaration of Helsinki and Council for International 
Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations.  Each trial site will seek 
approval/favorable opinion by an IRB or IEC according to regional 
requirements, and the investigator will provide that documentation 
to the sponsor.  


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12 
Confidentiality:
...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.
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 IMPs, 
subject bodily fluids, and/or other materials collected shall be used 
solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject 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.
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/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 IMP(s) 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 


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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.
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:
New section for this amendment
Appendix 2:
Phone 
 
Mobile 
E-Mail 
Study Communications & Patient/Site
Support
 
Phone: 
s
Phone 
; Mobile 
Fax:  
E-Mail: 
Study Communications & Patient/Site
Support
 
Phone: 
IDMC Support
Phone:  
Fax:  


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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 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.
...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.


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_____________________________________________
Principal or Coordinating Investigator Signature and Date
_____________________________________________
Sponsor Representative Signature and Date
____________________________
Principal Investigator 
____________________________
Print Name
____________________________
Signature
____________________________
Date
ADDITIONAL RISK TO THE SUBJECT:  There is no additional risk to the subjects.


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Amendment 5, 17 Nov 2015
Amendment Number:
4
Issue Date:
07 May 2015
PURPOSE:

Correction of typographical errors in the dosing table (Table 2.1.1-2) for the 
suspension for subjects taking a CYP3A inhibitor.

Removed the word “Tablet” from the title of Table 2.1.1-2 as the table includes 
dosing information for tolvaptan tablets and for the suspension formulation of 
tolvaptan.

Updated the Clinical Management contact information on the title page and in 
Appendix 1.

Correction of typographical error in Section 2.1.1 Dosing Rationale.
BACKGROUND:
Table 2.1.1-2 was added to this protocol with Amendment Number 3.  Subsequent to the 
approval of Amendment Number 3, typographical errors were discovered in 
Table 2.1.1-2.  The errors are being corrected with this protocol amendment (Amendment 
Number 4).
The Clinical Management contact information has been updated.
A typographical error in Section 2.1.1 Dosing Rationale has been corrected.  The word 
“staring” has been corrected to “starting”.
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     
           
           Phone 
; 
                                        Fax 
           E-mail:  
Issue Date:
03 Jul 2013
Date of Amendment 1:
04 Nov 201
Date of Amendment 2:
19 May 2014
Date of Amendment 3:
26 February 2015
Clinical Management    
          
          Phone 
; 
                                       Fax 
          E-mail:  
                                                           
Issue Date:
03 Jul 2013
Date of Amendment 1:
04 Nov 201
Date of Amendment 2:
19 May 2014
Date of Amendment 3:
26 February 2015
Date of Amendment 4:
07 May 2015
2.1.1 
Dosing 
Rationale:
...
Subjects ≥ 2 years of age, weighing ≤30 kg and who cannot safely 
swallow a tablet, will receive an oral, once daily dose of tolvaptan 
suspension staring at 0.15 mg/kg.  
...
Subjects ≥ 2 years of age, weighing ≤30 kg and who cannot safely 
swallow a tablet, will receive an oral, once daily dose of tolvaptan 
suspension starting at 0.15 mg/kg.  
Old Text:  Table 2.1.1-2
Table 2.1.1-2 Starting Tolvaptan Tablet Doses in the Presence of Potent or 
Moderate CYP3A Inhibitors
Tolvaptan Dose
Age/Body Weight (as 
applicable)
Potent Inhibitor
Moderate Inhibitor
0.1 mg/kg 
suspensiona
44 wk to < 2 y or 
< 10 kg
-
0.05 mg/kg suspension
0.15 mg/kg 
suspension
2 y, ≤ 30 kg
0.04 mg/kg suspension
0.8 mg/kg suspension
3.75 mg tablet
10 kg to < 20 kg  
0.94 mL suspension
0.19 mL suspension
7.5 mg tablet
20 kg to 50 kg
1.90 mL suspension
3.75 mg tablet 
15 mg tablet
50 kg
3.75 mg tablet
7.5 mg tablet
aThe smallest volume of suspension that may be administered is 0.3 mL (0.3 mg), therefore dose reductions for potent inhibitors cannot be accommodated and 
for moderate inhibitors children weighing < 6 kg cannot be accommodated.


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Updated Text:  Table 2.1.1-2
Table 2.1.1-2 Starting Tolvaptan Doses in the Presence of Potent or Moderate 
CYP3A Inhibitors
Tolvaptan Dose
Age/Body Weight (as 
applicable)
Potent Inhibitor
Moderate Inhibitor
0.1 mg/kg 
suspensiona
44 wk to < 2 y or 
< 10 kg
-
0.05 mg/kg suspension
0.15 mg/kg 
suspension
2 y, ≤ 30 kg
0.04 mg/kg suspension
0.08 mg/kg suspension
3.75 mg tablet
10 kg to < 20 kg  
0.94 mL suspension
1.90 mL suspension
7.5 mg tablet
20 kg to 50 kg
1.90 mL suspension
3.75 mg tablet 
15 mg tablet
50 kg
3.75 mg tablet
7.5 mg tablet
aThe smallest volume of suspension that may be administered is 0.3 mL (0.3 mg), therefore dose reductions for potent inhibitors cannot be accommodated and 
for moderate inhibitors children weighing < 6 kg cannot be accommodated.
Location
Old Text
Updated Text
Appendix 1:
Phone 
; Fax 
Phone 
; Fax 
ADDITIONAL RISK TO THE SUBJECT:  There is no additional risk to the subjects.


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Amendment 5, 17 Nov 2015
Amendment Number:
5
Issue Date:
17 Nov 2015
PURPOSE:
The main intent of the Amendment is to clarify administrative sections, align with current 
protocol templates, and incorporate recent requests from Regulatory Authorities (Food 
and Drug Administration [FDA]).
BACKGROUND:
This protocol serves as the single trial for the Pediatric Written Request with the FDA 
and the Pediatric Research Equity Act (PREA) requirement for the US. The FDA has 
agreed to the current version of the protocol and updates have been made to address 
further comments from the FDA, and other regulatory agencies.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Removed the neurocognition test battery. This was an exploratory endpoint and 
the removal of the neurocognition test battery has no impact on the safety aspects 
of the trial. 

Clarified dosing as dual formulations are employed:  tablet and suspension.

Alignment within the protocol descriptor sections of time points for 
pharmacokinetic assessments and serum sodium assessments; no change to 
requirement of time points or assessments.

Clarification of Exclusion Criteria and added an exclusion criterion to reflect the 
suspension use and protocol template update.

Removed reference to the extension study, 156-11-294.

Standard Protocol template updates made to reflect Investigator’s Brochure (IB)
Edition 21 issuance.

Clarified requirements for a full versus directed physical examination and 
neurological examination.  Added a fontanelle assessment as age appropriate.

Clarified urine vs. serum pregnancy test requirements.

FE urate changed to FE urea throughout the protocol.

Urine uric acid changed to urine urea throughout the protocol.

Provided additional information related to the Tanner Staging Assessment, 
including an Appendix for classification reference.

Updated the protocol template to make consistent with changes in the Phase 3 
global protocol template (ie. revised definition of AE, SAE definition related to 
hospitalization, IRE definition, including potential DILI, Clinical lab test value 
changes, IMP Causality, Eliciting and Reporting AEs).

Clarified pregnancies to be reported to INC Research instead of the sponsor.


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
Clarified the time points in which nonserious and serious AEs will be followed.

Updated list of abbreviations and references.
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.


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Amendment 5, 17 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 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 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


Otsuka Pharmaceutical Development & Commercialization, Inc.
This page is a manifestation of an electronically captured signature
                                                                                                                                
SIGNATURE PAGE
Document Name:
Document Number:
Document Version:
Signed by
Meaning of Signature
Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
OPC-41061
156-08-276 Protocol Amendment 5
0001027730
9.0
Biostatistics Approval
17-Nov-2015 21:03 GMT+00
Clinical Pharmacology
17-Nov-2015 21:46 GMT+00
Clinical Approval
18-Nov-2015 03:34 GMT+00

SAP_001.pdf: 
Protocol: 156-08-276 
Confidential - Proprietary Information 
 Protocol number: 156-08-276. 
 Document title: A Phase 3b, Multicenter, Open-label, Randomized 
Withdrawal Trial of the Effects of Titrated Oral SAMSCA® (Tolvaptan) on 
Serum Sodium, Pharmacokinetics, and Safety in Children and Adolescent 
Subjects Hospitalized With Euvolemic or Hypervolemic Hyponatremia 
 Version number: SAP Amendment 5. 
 Date of the document: 17 Nov 2015. 
 EudraCT number: 2013-002005-59. 


Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational New Drug 
OPC-41061
A Phase 3b, Multicenter, Open-label, Randomized Withdrawal Trial of the Effects of 
Titrated Oral SAMSCA(Tolvaptan) on Serum Sodium, Pharmacokinetics, and Safety in 
Children and Adolescent Subjects Hospitalized With Euvolemic or 
Hypervolemic Hyponatremia
Protocol No. 156-08-276
IND No. 54,200
NDA No. 22-275
EudraCT No. 2013-002005-59
Statistical Analysis Plan
Date: 16 Aug 2017
Protocol Version 1.0: 03 Jul 2013
Protocol Amendment 01: 04 Nov 2013
Protocol Amendment 02: 19 May 2014
Protocol Amendment 03: 26 Feb 2015
Protocol Amendment 04:  07 May 2015
Protocol Amendment 05: 17 Nov 2015
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.


Confidential - Proprietary Information
2
16 Aug 2017
Table of Contents
Table of Contents...........................................................................................2
List of In-text Tables .....................................................................................4
1
Introduction ..........................................................................................5
2
Trial Objective......................................................................................5
3
Trial Design...........................................................................................5
3.1
Treatment Phase A ............................................................................................. 5
3.2
Treatment Phase B.............................................................................................. 5
3.3
Follow-up Phase C ............................................................................................. 6
4
Sample Size and Power Justification..................................................6
4.1
Sample Size for Efficacy.................................................................................... 6
4.2
Sample Size for Pharmacokinetic Parameters.................................................... 7
5
Statistical Methods ...............................................................................7
5.1
Efficacy Analysis ............................................................................................... 7
5.1.1
Data Sets Analyzed.......................................................................................... 7
5.1.2
Handling of Missing Data................................................................................ 8
5.1.3
Randomization................................................................................................. 8
5.1.4
Baseline Characteristics and Baseline Comparability..................................... 8
5.1.5
Treatment Compliance..................................................................................... 9
5.1.6
Protocol Deviations ......................................................................................... 9
5.1.7
Primary Outcome Analysis.............................................................................. 9
5.1.7.1
Analysis of the Primary Outcome Endpoint ................................................ 9
5.1.7.2
Technical Computational Details for Primary Outcome Analysis............. 10
5.1.7.3
Subgroup Analysis of the Primary Outcome Endpoint.............................. 11
5.1.8
Secondary Outcome Analyses ....................................................................... 11
5.1.8.1
Analysis of the Key Secondary Endpoint .................................................. 11
5.1.8.2
Analyses of Other Secondary Endpoints.................................................... 11
5.1.8.3
Technical Computational Details for the Analysis of the Secondary 
Efficacy Endpoints..................................................................................... 12
5.1.9
Exploratory Efficacy Analysis....................................................................... 12
5.1.9.1
Analysis of Exploratory Efficacy Endpoints.............................................. 12


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5.1.9.2
Technical Computational Details for the Analysis of the Exploratory 
Efficacy Endpoints..................................................................................... 13
5.1.10
Analysis of Pharmacokinetic Parameters ...................................................... 14
5.2
Safety Analysis................................................................................................. 14
5.2.1
Duration of Exposure to Trial Medication..................................................... 15
5.2.2
Adverse Events .............................................................................................. 15
5.2.3
Laboratory Test Results................................................................................. 16
5.2.4
Vital Signs Data............................................................................................. 16
5.2.5
Electrocardiogram Data................................................................................. 16
5.2.6
Postbaseline Concomitant Medications......................................................... 16
5.3
Sample Size Re-estimation............................................................................... 17
6
Monitoring of Safety Data .................................................................17
7
SAP References...................................................................................17


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List of In-text Tables
Table 5.3-1
Sample Size Re-estimation ............................................................17


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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 156-08-276. All amendments to the protocol are taken 
into consideration in developing this SAP.
This SAP is prepared with protocol version Amendment 5, dated 17 Nov 2015.
2
Trial Objective
The primary objective is to demonstrate that tolvaptan effectively and safely increases 
and maintains serum sodium concentrations in children and adolescent subjects with 
euvolemic or hypervolemic hyponatremia.
The key secondary objective is to assess the pharmacokinetics (PK) of tolvaptan and the 
effect on fluid balance in children and adolescent subjects with euvolemic or 
hypervolemic hyponatremia.
3
Trial Design
This is an open-label, multicenter, multiple-dose, randomized withdrawal, parallel-group 
trial of tolvaptan in children and adolescents hospitalized with chronic euvolemic or 
hypervolemic hyponatremia (serum sodium < 130 mEq/L [mmol/L]) persisting despite 
initial standard therapy.  
3.1
Treatment Phase A 
All subjects will initially receive tolvaptan once daily on Days 1 and 2.  If a subject’s 
serum sodium level has not increased by at least 4 mEq/L (mmol/L) by end of Day 2, an 
additional day of treatment is required and is referred to as Day 2a. If subjects do not 
achieve an increase in serum sodium concentration of ≥4 mEq/L (mmol/L) on Day 2a, 
they will be defined as nonresponders. If subjects achieve an increase in serum sodium 
concentration of 4 mEq/L (mmol/L) on end of Day 2 (or 2a), they will be defined as
responders.  
3.2
Treatment Phase B 
On Day 3, responders will be randomized to either the Early Withdrawal group or the 
Late Withdrawal group. Subjects in the Late Withdrawal group continue tolvaptan 
treatment on Days 3 and 4, subjects in the Early Withdrawal group do not receive 
additional tolvaptan treatment on Days 3 and 4. Nonresponders will not be randomized.


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For nonresponders from Treatment Phase A, the investigator will determine if the subject 
is to either: 

Continue treatment with IMP for Days 3 and 4, or 

Prescribe treatment per local standard of care for Days 3 and 4.
Randomization will be stratified by age 
, serum 
sodium response 
, and underlying hyponatremia etiology
 
Subjects randomized to the Early Withdrawal group will be observed to determine 
whether additional intervention is required to maintain appropriate serum sodium levels.  
Subjects whose serum sodium declines by ≥4 mEq/L (mmol/L) or whose overall clinical 
condition requires further treatment to raise serum sodium levels should be treated per 
local standard of care.  Any intervention intended to raise serum sodium concentration 
during the first 48 hours of Treatment Phase B (including fluid restriction) will be defined 
as rescue therapy.  Subjects receiving rescue therapy will be considered to have reached 
their clinical endpoint, and their data will be censored from that time forward.
3.3
Follow-up Phase C
All subjects will have an additional serum sodium measurement at 72 (± 4) hours 
post-last dose and 7 (+ 1) days post-last dose.  A final safety follow-up telephone 
contact/visit will be performed 14 (+ 2) days post-last dose.
4
Sample Size and Power Justification
4.1
Sample Size for Efficacy
A total of 70 randomized subjects will provide 90% power to detect a treatment 
difference of 4 mEq/L (mmol/L) in change in serum sodium from Day 2 (or 2a) at the 
end of Treatment Phase A to the end of Treatment Phase B using a 2-sided alpha of 0.05.  
A standard deviation (SD) of 5 in change of serum sodium was used for the sample size 
calculation.  After the end of Treatment Phase A at Day 2 (or 2a), subjects will be 
randomized at a ratio of 1:1 to either continue treatment with tolvaptan for 2 additional 
days (Late Withdrawal) or to discontinue tolvaptan treatment (Early Withdrawal).  
Sample size re-estimation will be conducted when 90% of the randomized subjects finish 
(complete or discontinue) the trial.


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4.2
Sample Size for Pharmacokinetic Parameters
The sample size to establish similarity between the confidence intervals (CIs) for 
PK parameter estimates in adults and pediatrics is based on PK data of clearance.  
 
  To be conservative, it is assumed that 
the coefficient of variation (CV) of clearance is 0.42.  In order to establish a 95% CI 
within 60% and 140% of the point estimate for the geometric mean estimate of clearance 
in an age group (age < 10 or ≥10 years), under the assumption that the geometric mean 
estimates of clearance are equal between adult and pediatric subjects, CIs of the ratio of 
geometric means of pediatrics and adults will be constructed.  Twenty pediatric subjects 
and 80 adult subjects are needed to have 90% power to establish a 95% CI of the ratio of 
geometric means within 0.71 and 1.40.  In the actual analysis, all 81 adult subjects’ data
will be used.
5
Statistical Methods
5.1
Efficacy Analysis
Due to the extremely low enrollment to the trial and its early termination status, the 
efficacy analyses specified in the SAP do not need to be conducted in the final analysis, 
except providing summary statistics.
5.1.1
Data Sets Analyzed
The following samples are defined for this trial:

Treatment Phase A Safety Sample consists of all subjects who receive at least one 
dose of investigational medicinal product (IMP) in Treatment Phase A of the trial.

Treatment Phase B Safety Sample for responders consists of all randomized Late 
Withdrawal subjects who receive at least one dose of IMP in Treatment Phase B of 
the trial and all randomized Early Withdrawal subjects.

Treatment Phase B Safety Sample for nonresponders consists of all nonresponders
who receive at least one dose of IMP or standard of care in Treatment Phase B of the 
trial.

Treatment Phase A Efficacy Sample consists of all subjects who are in the Treatment 
Phase A Safety Sample and have baseline and at least one postbaseline serum sodium
evaluation in Treatment Phase A.

Treatment Phase B Efficacy Sample for the responders is based on the intent-to-treat 
(ITT) principle; the full analysis dataset will be composed of all subjects who are in 
the Treatment Phase B Safety Sample and have both baseline and at least one 
postrandomization serum sodium evaluation in Treatment Phase B.


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
Treatment Phase B Efficacy Sample for the nonresponders consists of all subjects 
who are in the Treatment Phase B Safety Sample for nonresponders and have both 
baseline and at least one postbaseline serum sodium evaluation in Treatment Phase B.
The core dataset for efficacy analyses will be based on the ITT population.  In order to 
handle missing data and restrictions imposed by different types of analyses (eg, change 
from baseline analysis), datasets derived from the ITT dataset will be used for the 
efficacy analyses.
5.1.2
Handling of Missing Data
For the primary endpoint analysis, missing data will be handled by analysis of 
mixed-model repeated measures (MMRM) methodology under the assumption of missing 
at random.  The MMRM analysis will be performed based on the observed cases (OC) 
data.  In order to assess sensitivity of results due to missing data, the last observation 
carried forward (LOCF) analysis will be performed as a sensitivity analysis.  In contrast 
to the OC dataset, which will consist of the actual observations recorded at each visit, the 
LOCF dataset will include data recorded at a scheduled visit (ie, all OC data, or, if no 
observation is recorded at that visit, data carried forward from the previously scheduled 
visit).  Baseline data will not be carried forward to impute missing values for the LOCF 
dataset.
5.1.3
Randomization
Eligible subjects will be randomized in a 1:1 ratio to either the Early Withdrawal group 
or the Late Withdrawal group. Randomization will be stratified by age 
 
, serum sodium response 
, and 
underlying hyponatremia etiology 
 
.
5.1.4
Baseline Characteristics and Baseline Comparability
In general, baseline measurements of efficacy and safety variables are defined as their 
last measurements prior to the first dose of IMP in the corresponding phases.
Demographic characteristics and medical history at Screening will be summarized by 
descriptive statistics, eg, proportion, mean, median, SD, minimum and maximum values.  
Use of concomitant medications prior to the start of IMP will be summarized by number 
and percentage of users by treatment group.  These summary statistics will be reviewed 
to identify any potential lack of balance between the treatment groups.
Baseline characteristics will be summarized for Treatment Phase A and Treatment 
Phase B, respectively. Baseline characteristics by age categories 
 


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 and by disease etiology
will also be provided.
5.1.5
Treatment Compliance
Treatment compliance will be calculated by dividing the total dose taken by the total dose 
the subjects are scheduled to take during the trial. For the Early Withdrawal subjects, the 
subjects are not scheduled to take the IMP in Treatment Phase B, the compliance will be 
100% for these subjects unless they accidentally take the IMP.
5.1.6
Protocol Deviations
Major protocol deviations data will be summarized by type of deviations (eg, deviations 
in entry criteria, dosing, randomization, concomitant medication, procedural, etc) by 
center and treatment group. In addition, a subject listing will be provided describing the 
deviations for each subject.
5.1.7
Primary Outcome Analysis
5.1.7.1
Analysis of the Primary Outcome Endpoint
The primary endpoint in this trial is the change in serum sodium level for responders 
from Day 2 (or 2a) at the end of Treatment Phase A (where all subjects receive tolvaptan) 
to the end of Treatment Phase B for the Early compared to Late Withdrawal groups.  The 
null hypothesis of this comparison is that there is no difference between the Late and the 
Early Withdrawal groups in change of serum sodium level from Day 2 (or 2a) at the end 
of Treatment Phase A to the end of Treatment Phase B.  The analysis of the primary 
endpoint is based on the Treatment Phase B Efficacy Sample.  Once a subject is 
randomized to Treatment Phase B, any additional therapies for the purpose of raising 
serum sodium, including fluid restriction, will be considered rescue therapy.  Upon 
receipt of rescue therapy, a subject’s endpoint data will be collected and then censored
from the efficacy analysis thereafter unless specified.  The primary analysis of this 
protocol is based on the data collected in this manner.
A sensitivity analysis will be provided in which serum sodium data collected for an 
Early Withdrawal subject under fluid restriction will not be censored for the analysis of
the primary endpoint.  This sensitivity analysis would become the primary analysis if at 
least 30% of the Early Withdrawal subjects do not have serum sodium data at 24 and 
48 hours postrandomization due to application of fluid restriction in the withdrawal phase 
of the protocol.
The MMRM analysis with an unstructured variance covariance structure based on the 
OC dataset will be performed on the primary endpoint.  The MM
clude 


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fixed effect of treatment, age subgroup 
, serum 
sodium response subgroup 
, underlying etiology 
 
, visit, treatment visit 
interaction, and covariate of baseline and baseline visit interaction.  A statistical test of 
the least squares (LS) mean differences between treatment groups at the end of Treatment 
Phase B of the MMRM analysis will serve as the primary analysis.
As a sensitivity analysis, analysis of covariance (ANCOVA) with baseline value as 
covariate and treatment, age subgroup, serum sodium response subgroup, and underlying 
etiology of hyponatremia as factors will be applied to the LOCF dataset.  Treatment 
comparison between the Late and Early Withdrawal groups will be conducted by 
comparing their LS.
5.1.7.2
Technical Computational Details for Primary Outcome Analysis
1) Baseline for Treatment Phase B is the last evaluation of serum sodium at the end of 
Treatment Phase A.
2) For the Early Withdrawal group, the serum sodium collected at 72 hours post-last 
dose on the CRF will be used to define the endpoint of Treatment Phase B. For the 
Late Withdrawal group, the serum sodium collected at 24 hours post-dose (Trough) 
of Day 4 on the CRF will be used to define the endpoint of Treatment Phase B.
3) The MMRM analysis for the primary endpoint will be analyzed using PROC MIXED 
of SAS (with default REML option).  Specifically, the following SAS statements will 
be used for the primary analysis:
proc mixed;
class treatment visit subject agesubgrp responsesubgrp etiologysubgrp;
model change =agesubgrp responsesubgrp etiologysubgrp treatment  visit 
treatment*visit  baseline baseline*visit/ s ddfm=kr;
repeated visit / type=un sub=subject;
lsmeans treatment*visit / pdiff cl alpha=0.05;
run;
4) In case there is a convergence problem in the MMRM model with the unstructured 
variance covariance matrix, the following variance covariance matrix structures will 
be used in the order of 1) heterogeneous toeplitz, 2) heterogeneous autoregressive of 
order 1, and 3) heterogeneous compound symmetry.  The first (co)variance structure 
which does not have a convergence problem will be the one used for the analysis. If a 
structured covariance has to be used, the “sandwich” estimator of the variance 
covariance matrix of the fixed effects parameters will be used in order to deal with 
possible model misspecification of the covariance matrix.
5) Medications for rescue therapy (with indication of hyponatremia) include:
Rescue therapy is defined as any level of fluid restriction, hypertonic saline, isotonic 
saline (with or without diuretic for purpose of increasing the serum sodium level), 
plasmapheresis/dialysis, demeclocycline, urea, lithium, commercially available 


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vaptans, or any treatment intended to raise the level of serum sodium at any time 
during the trial.
5.1.7.3
Subgroup Analysis of the Primary Outcome Endpoint
Subgroup analysis of the primary efficacy endpoint will be conducted by gender and race 
(white and all other races), using similar analysis of the primary analysis.  The subgroup 
analysis by 3 stratification factors will also be provided for the primary endpoint.
Subgroup analysis by additional age categories 
 
will also be provided for the primary endpoint.
5.1.8
Secondary Outcome Analyses
5.1.8.1
Analysis of the Key Secondary Endpoint
For all subjects, the key secondary endpoint is the change from baseline in serum sodium 
concentration at the end of Day 2 (or 2a) at the end of Treatment Phase A.  The analysis 
of the key secondary endpoint will be based on the Treatment Phase A Efficacy Sample.
A paired Student’s t-test will be used to analyze the key secondary endpoint.
For the key secondary efficacy analysis, a hierarchical testing procedure will be used to 
maintain the overall experiment-wise type I error rate at 0.05.  Thus, if the primary 
efficacy analysis yields a statistically significant result at an alpha level of 0.05 (2-sided), 
then the paired t-test will be performed at an alpha level of 0.05 for the key secondary 
endpoint.
Baseline for the key secondary analysis is the last evaluation prior to first dose of IMP in 
Treatment Phase A.
5.1.8.2
Analyses of Other Secondary Endpoints
Other secondary endpoints include:

Percentage of subjects with an overly rapid increase in serum sodium level
.

Change in serum sodium level from 24 hours post-last dose to 7 days post-last dose.

Percentage of subjects requiring rescue therapy (other than fluid restriction) during 
Treatment Phase A and Treatment Phase B.

Percentage of subjects requiring fluid restriction during Treatment Phase A and 
Treatment Phase B.

Pharmacodynamic endpoints are fluid intake, urine output, and fluid balance 
(intake minus output) every 6 hours on Days 1 and 2 in Treatment Phase A.


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Descriptive statistics along with 2-sided 95% CIs will be applied for the percentage of 
subjects with an overly rapid increase in serum sodium and for the percentage of subjects 
requiring rescue therapy or fluid restriction.
The change in serum sodium level from 24 hours post-last dose to 7 days post-last dose
will be summarized using a paired Student’s t-test.
Urine volume will be summarized by 6-hour intervals using descriptive statistics.  Fluid 
intake and the calculated value of fluid balance will be summarized for each 6-hour 
period and for the 24-hour daily interval on Days 1 and 2 in Treatment Phase A using 
descriptive statistics.  A subgroup analysis by the disease etiology of hyponatremia or by 
fluid status (euvolemic, hypervolemic) may be conducted if there are sufficient subjects 
in each category.
5.1.8.3
Technical Computational Details for the Analysis of the 
Secondary Efficacy Endpoints
1) Percentage of subjects with an overly rapid increase in serum sodium level will only 
apply to the Treatment Phase A Efficacy Sample.
2) Change in serum sodium level from 24 hours post-last dose to 7 days post-last dose 
will only apply to the Treatment Phase B Efficacy Sample for responders.
5.1.9
Exploratory Efficacy Analysis
5.1.9.1
Analysis of Exploratory Efficacy Endpoints
Exploratory analyses will include:

Change in Serum Sodium level from baseline at the end of Treatment Phase B 
compared to the end of Treatment Phase A for nonresponders continuing on tolvaptan 
therapy

Quality of life (QoL) assessments

In all subjects, 24-hour excretion of sodium, creatinine, and osmolality on Days 1 and 
2

24-hour sodium clearance on Day 1
A paired Student’s t-test will be applied to the change from baseline in serum sodium 
concentration for nonresponders continuing on tolvaptan therapy.
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 by the paired Student’s t-test for the responders. For the 


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QoL MFS, the QoL MFS total score will be analyzed by the paired Student’s t-test for the 
responders.
For the responders, the change from baseline at the end of Treatment Phase A to the end
of the Treatment Phase B will be compared between the Early Withdrawal group and the 
Late Withdrawal group using the same MMRM analysis that is used for the primary 
endpoint.
Urine osmolality and urine creatinine, potassium, and sodium concentrations will be 
summarized by collection interval and for zero to 24 hours on Days 1 and 2 in Treatment 
Phase A using descriptive statistics.
5.1.9.2
Technical Computational Details for the Analysis of the 
Exploratory Efficacy Endpoints
1) In Treatment Phase A, subjects achieving an increase in serum sodium concentration 
of ≥4 mEq/L (mmol/L) by end of Day 2 (or 2a) will be defined as responders.  If 
subjects do not achieve an increase in serum sodium concentration of ≥4 mEq/L 
(mmol/L) by end of Day 2 (or 2a), they will be defined as nonresponders.  
2) 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 to 100 scale, so that higher scores indicate better HRQOL (Health-Related Quality 
of Life). 
To reverse score, transform the 0 to 4 scale items to 0 to 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. 
3) 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 to 100 scale as follows: 
0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0.


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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. 
4) Missing urine concentrations or volumes will not be imputed.  All calculations will 
use nominal times.
If urine volume during a collection interval is zero, then the amount excreted for that 
interval will be set to missing; values for 24 hours will be determined.
5.1.10
Analysis of Pharmacokinetic Parameters
To establish similarity between the CIs for PK parameter estimates between adults and 
pediatrics based on PK data of clearance, the clearance data of at least 20 pediatric 
subjects from this trial and 81 adult subjects from an existing tolvaptan trial will be used.
An analysis of variance model will be performed on the natural log transformed PK 
parameters using the MIXED procedure in SAS, in which only one fixed effect of subject 
group (pediatric and adult groups) is included in the model. From each analysis, least 
squares means, their difference, and the 90% CI for their difference will be derived.  
Then, the antilogs of the difference and the confidence limits will provide the estimate 
and 90% CI for the ratio of the geometric means of the 2 treatments (pediatric vs adult).
The similarity of PK parameter estimates between adults and pediatrics will be claimed if 
the 90% CI for the ratio of the population geometric meansbased on the analysis of the 
log-transformed datais contained within the confidence limits of 0.60 to 1.40.
5.2
Safety Analysis
The safety analysis will be conducted based on the Safety Samples, which are defined in 
Section 5.1.1.  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.
Safety analyses will be performed for Treatment Phase A and Treatment Phase B 
separately. Safety analyses by age categories 
 
 will be provided as well.


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5.2.1
Duration of Exposure to Trial Medication
Duration of exposure to each treatment of each subject will be summarized by treatment 
group.  A subject’s duration of exposure is defined as the IMP end date −IMP 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 IMP in this trial that was not present prior to IMP
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.
Safety variables of analysis include:

Proportion of subjects with TEAEs

Proportions of subjects with TEAEs by preferred term

Proportion of subjects with severe TEAEs

Proportion of subjects with serious TEAEs

Proportion of subjects with TEAEs leading to death

Proportion of subjects with potentially drug-related TEAEs

Proportion of subjects with TEAEs that result in trial termination
Analysis of special interested AEs include:

Proportion of subjects with absolute serum sodium level ≥145 mEq/L

Proportion of subjects with overly rapid rise in serum sodium defined as an 
increase in serum sodium of 
or a rate of increase 
in serum sodium that the investigator deems too rapid

Proportion of subjects with neurological symptoms or other signs or symptoms 
suggestive of osmotic demyelination

Proportions of subjects with worsening symptoms of hyponatremia

Proportion of subjects with hypovolemia or hypotension requiring intervention
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 postbaseline 
visits, and summary statistics of changes from baseline to each visit will be presented by 
treatment group. Shift tables will be produced, assessing low-normal-high (at baseline) 
to low-normal-high (at postbaseline visit). 
The incidence of treatment-emergent potentially clinically significant abnormal 
laboratory results will also be summarized by treatment groups.  Listings of potentially 
clinically significant abnormalities will also be provided.
According to the Food and Drug Administration (FDA) 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 by treatment group, for both vital signs and change 
from baseline in vital signs. The incidence of treatment-emergent potentially clinically 
significant vital sign results will also be summarized by treatment groups. Listings of 
potentially clinically significant abnormalities will also be provided. 
For a subject with repeat measures in either vital signs or laboratory 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 ECG data will be collected 
at the screening visit only.
5.2.6
Postbaseline Concomitant Medications
Concomitant medications used postbaseline will be summarized in two categories of time 
interval:  during the IMP period and after the IMP period. In each case, the use of 
concomitant medications will be summarized by number and percentage of users by 
treatment group.


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5.3
Sample Size Re-estimation
It was recommended by the FDA that the sample size should be re-estimated when 
approximately 90% of the subjects had finished the trial.  The sample size re-estimation 
will assess the variability of change from Day 2 (or 2a) at the end Treatment Phase A to 
the end of Treatment Phase B in serum sodium level by using the pooled variance of the 
2 treatment groups.  At the trial planning stage, an SD of 5 was used to detect a treatment 
difference of 4, resulting in a sample size of 70 with a 2-sided alpha of 0.05 and 
90% power.  In case the variance ratio (equal to the observed pooled variance divided by 
25, the square of 5 as an SD used in the sample size calculation) is ≤1, no sample size 
increase will be made, and the trial will proceed to finish enrollment of 70 randomized 
subjects.  In case the variance ratio is > 1, the sample size re-estimation will be equal to 
70 multiplied by the variance ratio, then rounded up to the nearest even number.  
Table 5.3-1 provides an example of the sample size re-estimation under different variance 
ratios.
Table 5.3-1
Sample Size Re-estimation
Variance Ratio
Sample Size
1.1
78
1.2
84
1.3
92
1.4
78
1.5
106
6
Monitoring of Safety Data
Safety monitoring will be performed by the Independent Data Monitoring Committee
(IDMC). Reference is made to the IDMC Charter for details of constituents and roles and 
responsibilities of IDMC.  The independent statistician at Theorem will work closely 
with the IDMC and will assist the IDMC in the retrieval and analysis of safety and 
efficacy data. The DMC will review the data periodically.  Summary tables will be 
produced by OPDC (Otsuka Pharmaceutical Development & Commercialization) 
Biometrics. 
7
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.


Otsuka Pharmaceutical Development & Commercialization, Inc.
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OPC-41061
P15608276_SAP
0001127440
6.0
Clinical Approval
25-Aug-2017 19:06 GMT+00
Biostatistics Approval
28-Aug-2017 18:03 GMT+00