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

NCT02012959 | Terminated Phase 3 Results DMC

• 2 other identifiers: 156-08-2762013-002005-59
• Study Type: interventional
• Target: 9
• Locations: 3 countries
• Sites: 7

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.

Conditions

Hyponatremia

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

  Day 2/2a, Day 4

Secondary Outcomes (2)

• Change In Serum Sodium Concentration During Treatment Phase A

  Baseline, Day 2/2a

• Fluid Balance (Intake Minus Output) During Treatment Phase A

  Every 6 hours on Days 1 and 2

Study Arms (2)

Tolvaptan Early Withdrawal

EXPERIMENTAL

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.

Drug: Tolvaptan

Tolvaptan Late Withdrawal

EXPERIMENTAL

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.

Drug: Tolvaptan

Interventions

Tolvaptan DRUG

Also known as: SAMSCA®

Tolvaptan Early Withdrawal; Tolvaptan Late Withdrawal

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead
• Syneos Health: collaborator

Study Sites (7)

Unknown Facility

Aurora, Colorado, 80045, United States

Location

Unknown Facility

Washington D.C., District of Columbia, 20010, United States

Location

Unknown Facility

New York, New York, 10032, United States

Location

Unknown Facility

Richmond, Virginia, 23298-0270, United States

Location

Unknown Facility

Seattle, Washington, 98105, United States

Location

Unknown Facility

Rome, 00165, Italy

Location

Unknown Facility

London, WC1N 3JH, United Kingdom

Location

MeSH Terms

Conditions

Hyponatremia; Metabolic Diseases

Interventions

Tolvaptan

Condition Hierarchy (Ancestors)

Water-Electrolyte Imbalance; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

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

Limitations and Caveats

Issues with recruitment and enrollment made trial execution highly impracticable. This ultimately led to termination of the trial. The study was not terminated due to safety reasons.

Results Point of Contact

• Title: Global Clinical Development
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.

clinicaltransparency@otsuka-us.com

+1-609-524-6788

Study Officials

• Global Clinical Development

  Otsuka Pharmaceutical Development & Commercialization, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 11, 2013
• First Posted: December 17, 2013
• Study Start: September 22, 2015
• Primary Completion: July 24, 2017
• Study Completion: July 24, 2017
• Last Updated: September 26, 2018
• Results First Posted: August 28, 2018

Record last verified: 2018-07

Locations

IT (1); US (5); GB (1)