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Study of the Safety and Effectiveness of SAMSCA® (Tolvaptan) in Children and Adolescents With Euvolemic or Hypervolemic Hyponatremia

Primary Purpose

Hyponatremia

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Tolvaptan
Sponsored by
Otsuka Pharmaceutical Development & Commercialization, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hyponatremia focused on measuring Hyponatremia, Euvolemic, Hypervolemic, Serum sodium, Dilutional hyponatremia, Electrolyte abnormality, Electrolyte imbalance, Metabolic disease

Eligibility Criteria

4 Weeks - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion:

  • Male and female participants ≥4 weeks (or ≥44 weeks adjusted gestational age) to <18 years old
  • Participants hospitalized with euvolemic or hypervolemic hyponatremia resistant to initial standard background therapy
  • Persistent euvolemic or hypervolemic hyponatremia defined as being documented as <130 milliequivalent (mEq)/L and present for at least 48 hours, evidenced by at least 2 serum sodium assessments (12 hours apart)
  • Ability to maintain adequate fluid intake (orally or intravenously)
  • Ability to take oral medications
  • Ability to comply with all requirements of the trial
  • Completion of the trial-specific informed consent/assent as age appropriate
  • Ability to commit to remain fully abstinent or practice double-barrier birth control as required by the trial

Exclusion:

  • Evidence of hypovolemia or intravascular volume depletion
  • Serum sodium <120 mEq/L
  • Use of potent cytochrome P450 3A4 (CYP3A4) inhibitors in participants <12 kilogram (kg) or moderate CYP3A4 inhibitors in participants <6 kg
  • Lacks free access to water (inability to respond to thirst) or without intensive care unit level fluid monitoring and management
  • History or current diagnosis of nephrotic syndrome
  • Transient hyponatremia likely to resolve
  • Hyperkalemia
  • Estimated glomerular filtration rate <30 milliliters/minute/1.73 meters squared
  • Acute kidney injury
  • Severe or acute neurological symptoms requiring other intervention
  • Prior treatment for hyponatremia with hypertonic saline within 8 hours of qualifying serum sodium assessments; urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of qualifying serum sodium assessments; any other treatments for the purpose of increasing serum sodium concurrent with dosing of trial medication
  • Anuria or urinary outflow obstruction, unless participant is/can be catheterized
  • History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives
  • Psychogenic polydipsia
  • Uncontrolled diabetes mellitus (defined as fasting glucose >300 milligrams/deciliter)
  • Screening liver function values >3 times the upper limit of normal
  • Participants who have cirrhosis and meet any of the following conditions: a major GI bleed within the past 6 months, evidence of active bleeding, platelet count <50,000/microliter, or use of concomitant medications known to increase bleeding risk
  • Hyponatremia due to the result of any medication that can safely be withdrawn or that is most appropriately corrected by alternative therapies
  • History of drug or medication abuse within 3 months prior to screening or current alcohol abuse
  • Participants who require suspension formulation and have a Hereditary Fructose Intolerance
  • Has hyponatremia that is more appropriately corrected by alternative therapies
  • Is pregnant or currently breastfeeding
  • Has any medical condition that could interfere with evaluation of trial objectives or participant safety
  • Has participated in another investigational drug trial in the last 30 days
  • Weighs <3 kg
  • Unable to swallow tablets, if suspension unavailable
  • Is deemed unsuitable for trial participation in the opinion of the investigator

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Tolvaptan Early Withdrawal

Tolvaptan Late Withdrawal

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Change In Serum Sodium Concentration For Responders
Change in serum sodium concentration (mEq/L) for responders from Day 2 (or Day 2a) at the end of Treatment Phase A (where all participants received tolvaptan) to the end of Treatment Phase B for the Early compared to Late Withdrawal groups is reported. Once a participant was randomized to Treatment Phase B, any additional therapies for the purpose of raising serum sodium, including fluid restriction, were considered rescue therapy. Upon receipt of rescue therapy, a participant's endpoint data was collected and then censored from the efficacy analysis thereafter, unless specified.

Secondary Outcome Measures

Change In Serum Sodium Concentration During Treatment Phase A
Change in serum sodium concentration (mEq/L) from baseline to the end of Day 2 (or 2a) during Treatment Phase A for all participants (responders and non-responders) is reported.
Fluid Balance (Intake Minus Output) During Treatment Phase A
Every 6 hours and for the 24-hour daily interval on Days 1 and 2 during Treatment Phase A, fluid balance (milliliters [mL]) was determined by fluid intake (oral and intravenous) minus urine output. Improved fluid balance would be indicated through the induction of increased urine volume. Fluid balance was monitored per institutional guidelines.

Full Information

First Posted
December 11, 2013
Last Updated
August 29, 2018
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
Syneos Health
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1. Study Identification

Unique Protocol Identification Number
NCT02012959
Brief Title
Study of the Safety and Effectiveness of SAMSCA® (Tolvaptan) in Children and Adolescents With Euvolemic or Hypervolemic Hyponatremia
Official 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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Terminated
Why Stopped
Issues with participant recruitment & enrollment which made the trial impossible or highly impracticable. Trial termination was not due to safety reasons.
Study Start Date
September 22, 2015 (Actual)
Primary Completion Date
July 24, 2017 (Actual)
Study Completion Date
July 24, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
Syneos Health

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyponatremia
Keywords
Hyponatremia, Euvolemic, Hypervolemic, Serum sodium, Dilutional hyponatremia, Electrolyte abnormality, Electrolyte imbalance, Metabolic disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tolvaptan Early Withdrawal
Arm Type
Experimental
Arm Description
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 Title
Tolvaptan Late Withdrawal
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Tolvaptan
Other Intervention Name(s)
SAMSCA®
Primary Outcome Measure Information:
Title
Change In Serum Sodium Concentration For Responders
Description
Change in serum sodium concentration (mEq/L) for responders from Day 2 (or Day 2a) at the end of Treatment Phase A (where all participants received tolvaptan) to the end of Treatment Phase B for the Early compared to Late Withdrawal groups is reported. Once a participant was randomized to Treatment Phase B, any additional therapies for the purpose of raising serum sodium, including fluid restriction, were considered rescue therapy. Upon receipt of rescue therapy, a participant's endpoint data was collected and then censored from the efficacy analysis thereafter, unless specified.
Time Frame
Day 2/2a, Day 4
Secondary Outcome Measure Information:
Title
Change In Serum Sodium Concentration During Treatment Phase A
Description
Change in serum sodium concentration (mEq/L) from baseline to the end of Day 2 (or 2a) during Treatment Phase A for all participants (responders and non-responders) is reported.
Time Frame
Baseline, Day 2/2a
Title
Fluid Balance (Intake Minus Output) During Treatment Phase A
Description
Every 6 hours and for the 24-hour daily interval on Days 1 and 2 during Treatment Phase A, fluid balance (milliliters [mL]) was determined by fluid intake (oral and intravenous) minus urine output. Improved fluid balance would be indicated through the induction of increased urine volume. Fluid balance was monitored per institutional guidelines.
Time Frame
Every 6 hours on Days 1 and 2

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Weeks
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion: Male and female participants ≥4 weeks (or ≥44 weeks adjusted gestational age) to <18 years old Participants hospitalized with euvolemic or hypervolemic hyponatremia resistant to initial standard background therapy Persistent euvolemic or hypervolemic hyponatremia defined as being documented as <130 milliequivalent (mEq)/L and present for at least 48 hours, evidenced by at least 2 serum sodium assessments (12 hours apart) Ability to maintain adequate fluid intake (orally or intravenously) Ability to take oral medications Ability to comply with all requirements of the trial Completion of the trial-specific informed consent/assent as age appropriate Ability to commit to remain fully abstinent or practice double-barrier birth control as required by the trial Exclusion: Evidence of hypovolemia or intravascular volume depletion Serum sodium <120 mEq/L Use of potent cytochrome P450 3A4 (CYP3A4) inhibitors in participants <12 kilogram (kg) or moderate CYP3A4 inhibitors in participants <6 kg Lacks free access to water (inability to respond to thirst) or without intensive care unit level fluid monitoring and management History or current diagnosis of nephrotic syndrome Transient hyponatremia likely to resolve Hyperkalemia Estimated glomerular filtration rate <30 milliliters/minute/1.73 meters squared Acute kidney injury Severe or acute neurological symptoms requiring other intervention Prior treatment for hyponatremia with hypertonic saline within 8 hours of qualifying serum sodium assessments; urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of qualifying serum sodium assessments; any other treatments for the purpose of increasing serum sodium concurrent with dosing of trial medication Anuria or urinary outflow obstruction, unless participant is/can be catheterized History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives Psychogenic polydipsia Uncontrolled diabetes mellitus (defined as fasting glucose >300 milligrams/deciliter) Screening liver function values >3 times the upper limit of normal Participants who have cirrhosis and meet any of the following conditions: a major GI bleed within the past 6 months, evidence of active bleeding, platelet count <50,000/microliter, or use of concomitant medications known to increase bleeding risk Hyponatremia due to the result of any medication that can safely be withdrawn or that is most appropriately corrected by alternative therapies History of drug or medication abuse within 3 months prior to screening or current alcohol abuse Participants who require suspension formulation and have a Hereditary Fructose Intolerance Has hyponatremia that is more appropriately corrected by alternative therapies Is pregnant or currently breastfeeding Has any medical condition that could interfere with evaluation of trial objectives or participant safety Has participated in another investigational drug trial in the last 30 days Weighs <3 kg Unable to swallow tablets, if suspension unavailable Is deemed unsuitable for trial participation in the opinion of the investigator
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Global Clinical Development
Organizational Affiliation
Otsuka Pharmaceutical Development & Commercialization, Inc.
Official's Role
Study Director
Facility Information:
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298-0270
Country
United States
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
City
Rome
ZIP/Postal Code
00165
Country
Italy
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

Study of the Safety and Effectiveness of SAMSCA® (Tolvaptan) in Children and Adolescents With Euvolemic or Hypervolemic Hyponatremia

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