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

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ClinicalTrials.gov Identifier: NCT02012959
Recruitment Status : Terminated (Issues with participant recruitment & enrollment which made the trial impossible or highly impracticable. Trial termination was not due to safety reasons.)
First Posted : December 17, 2013
Results First Posted : August 28, 2018
Last Update Posted : September 26, 2018
Sponsor:
Collaborator:
Syneos Health
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Tracking Information
First Submitted Date  ICMJE December 11, 2013
First Posted Date  ICMJE December 17, 2013
Results First Submitted Date  ICMJE July 31, 2018
Results First Posted Date  ICMJE August 28, 2018
Last Update Posted Date September 26, 2018
Actual Study Start Date  ICMJE September 22, 2015
Actual Primary Completion Date July 24, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 31, 2018)
Change In Serum Sodium Concentration For Responders [ Time Frame: Day 2/2a, Day 4 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 16, 2013)
Change in serum sodium concentration. [ Time Frame: Day 2/3, Day 4/5 ]
Change in serum sodium concentration.
Change History Complete list of historical versions of study NCT02012959 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 31, 2018)
  • Change In Serum Sodium Concentration During Treatment Phase A [ Time Frame: Baseline, Day 2/2a ]
    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 [ Time Frame: Every 6 hours on Days 1 and 2 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2013)
  • Change in serum sodium concentration. [ Time Frame: Day 2/3 ]
    Change in serum sodium concentration at the end of Day 2/3 from baseline in Phase A.
  • Overly rapid increase in serum sodium. [ Time Frame: 24 hours ]
    Percentage of subjects with overly rapid increase in serum sodium (≥12 mmol/L in 24 hours after 1st dose).
  • Percentage of subjects requiring rescue medication. [ Time Frame: Days 4/5 ]
    Percentage of subjects requiring rescue medication during Phase A and Phase B of the trial.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: December 16, 2013)
  • Change in serum sodium from 24 hours post-last dose to 14 days post-randomization. [ Time Frame: 14 days ]
    Change in serum sodium from 24 hours post-last dose to 14 days post-randomization.
  • Vital Signs of Potential Clinical Relevance - Mean Change from Baseline to study completion. [ Time Frame: 7 days ]
    Vital Signs of Potential Clinical Relevance - Mean Change from Baseline to study completion.
  • Tolvaptan plasma concentration. [ Time Frame: 24 hours ]
    Tolvaptan maximum (peak) plasma concentration, time to max (peak) plasma concentration, and area under the concentration-time curve from time zero to 24 hours.
  • Body Weight of Potential Clinical Relevance - Mean Change from Baseline to study completion. [ Time Frame: 7 days ]
    Body Weight of Potential Clinical Relevance - Mean Change from Baseline to study completion.
  • Blood Pressure of Potential Clinical Relevance - Mean Change from Baseline to study completion. [ Time Frame: 7 days ]
    Blood Pressure of Potential Clinical Relevance - Mean Change from Baseline to study completion.
  • Clinical Laboratory Tests of Potential Clinical Relevance - Mean Change from Baseline to study completion. [ Time Frame: 7 days ]
    Clinical Laboratory Tests of Potential Clinical Relevance - Mean Change from Baseline to study completion.
  • Fluid intake. [ Time Frame: Day 1/2 ]
    Fluid intake every 6 hours on Days 1 and 2 (Phase A).
  • Urine output. [ Time Frame: Day 1/2 ]
    Urine output every 6 hours on Days 1 and 2 (Phase A).
  • Fluid balance. [ Time Frame: Day 1/2 ]
    Fluid balance (intake - output) every 6 hours on Days 1 and 2 (Phase A).
 
Descriptive Information
Brief Title  ICMJE Study of the Safety and Effectiveness of SAMSCA® (Tolvaptan) in Children and Adolescents With Euvolemic or Hypervolemic Hyponatremia
Official Title  ICMJE 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
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 Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hyponatremia
Intervention  ICMJE Drug: Tolvaptan
Other Name: SAMSCA®
Study Arms  ICMJE
  • Experimental: Tolvaptan Early Withdrawal

    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.

    Intervention: Drug: Tolvaptan
  • Experimental: Tolvaptan Late Withdrawal

    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: Drug: Tolvaptan
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 25, 2017)
9
Original Estimated Enrollment  ICMJE
 (submitted: December 16, 2013)
100
Actual Study Completion Date  ICMJE July 24, 2017
Actual Primary Completion Date July 24, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy,   United Kingdom,   United States
Removed Location Countries Belgium,   Czech Republic,   Czechia,   Germany,   Romania,   Spain,   Turkey
 
Administrative Information
NCT Number  ICMJE NCT02012959
Other Study ID Numbers  ICMJE 156-08-276
2013-002005-59 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Otsuka Pharmaceutical Development & Commercialization, Inc.
Study Sponsor  ICMJE Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators  ICMJE Syneos Health
Investigators  ICMJE
Study Director: Global Clinical Development Otsuka Pharmaceutical Development & Commercialization, Inc.
PRS Account Otsuka Pharmaceutical Development & Commercialization, Inc.
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP