A Trial of Tolvaptan in Children and Adolescent Subjects With Euvolemic and Hypervolemic Hyponatremia

NCT02442674 | Withdrawn Phase 3 DMC

• 1 other identifier: 156-13-207
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this trial is to demonstrate that tolvaptan effectively and safely increases and maintains serum sodium concentrations in children and adolescent subjects with euvolemic or hypervolemic hyponatremia.

Conditions

Hyponatremia

Keywords

Hyponatremia; Euvolemic; Hypervolemic; Serum sodium; Dilutional hyponatremia; Electrolyte abnormality; Electrolyte imbalance; Metabolic disease; Water-Electrolyte Imbalance

Outcome Measures

Primary Outcomes (1)

• Change in serum sodium concentration

  The average daily area under the curve (AUC) of change from baseline in serum sodium level up to Day 4 within the double-blind treatment period.

  Daily up to day 4

Secondary Outcomes (9)

• Change of average daily AUC from baseline at each visit in serum sodium level.

  Daily up to Day 30

• Change from baseline in serum sodium concentration at Day 4.

  Day 4

• Change from baseline in serum sodium concentration at Day 30.

  Daily up to Day 30

• Percentage of subjects who require rescue therapy or fluid restriction at any time during the double-blind treatment period.

  Daily up to Day 30

• Changes from baseline in ALT, AST and Total Bilirubin

  Daily up to Day 30

Study Arms (2)

Tolvaptan

ACTIVE COMPARATOR

Tolvaptan (3.75 mg, 7.5 mg, 15 mg, 30 mg, 60 mg dose daily depending on age and weight)

Drug: Tolvaptan

Placebo

PLACEBO COMPARATOR

Placebo tablet matching active drug

Other: Placebo

Interventions

Tolvaptan DRUG

Tolvaptan 3.75-, 7.5-, 15-, and 30-mg Tablets. Dosage: Depending on age, weight and serum sodium response: Tablet (3.75 mg - 60 mg daily) Frequency: Once daily Duration: 30 (+2) days

Also known as: SAMSCA

Tolvaptan

Placebo OTHER

Placebo tablet matching active drug

Placebo

Eligibility Criteria

• Age: 4 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male and female subjects ≥ 4 years of age (or per local Health Authority age restriction) to \< 18 years old and ≥ 10kg
• 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
• Persistent euvolemic or hypervolemic hyponatremia defined as being documented as present for at least 48 hours, evidenced by at least 2 serum sodium assessments \< 130 mmol/L drawn at least 12 hours apart (these values can be documented using historical values previously obtained per standard of care); a third (STAT) serum sodium assessment \< 130 mmol/L, which will serve as the baseline value for efficacy endpoints, is to be obtained within 2-4 hours prior to the final trial qualification and the first dose of IMP
• Ability to swallow tablets
• Ability to maintain adequate fluid intake whether orally or via IV support with adequate monitoring
• Ability to comply with all requirements of the trial
• 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
• 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

You may not qualify if:

• 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
• Has serum sodium \< 120 mmol/L, with or without associated neurologic impairment (ie, symptoms such as apathy, confusion, or seizures)
• Subjects ≤ 50 kg taking potent CYP3A4 inhibitors or subjects \< 20 kg taking moderate CYP3A4 inhibitors within 72 hours prior to dosing
• Lacks free access to water (inability to respond to thirst) or without ICU-level fluid monitoring and management
• 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 ULN for the appropriate pediatric age range
• Has eGFR \< 30 mL/min/1.73 m2 calculated by the following equation:
• eGFR (mL/min/1.73 m2) = 0.413 x height (cm)/serum creatinine (mg/dL)
• Has AKI from recent medical history defined as:
• Increase in serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 µmol/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 severe or acute neurological symptoms requiring other intervention (eg, hyperemesis, obtundation, seizures)
• Has had treatment for hyponatremia with:

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

MeSH Terms

Conditions

Hyponatremia; Metabolic Diseases; Water-Electrolyte Imbalance

Interventions

Tolvaptan

Condition Hierarchy (Ancestors)

Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Ann Dandurand, MD

  Otsuka Pharmaceutical Development & Commercialization, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 8, 2015
• First Posted: May 13, 2015
• Study Start: November 1, 2015
• Primary Completion: June 22, 2017
• Study Completion: June 22, 2017
• Last Updated: July 31, 2017

Record last verified: 2017-07