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

Sponsors

Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Collaborator: Syneos Health

Source Otsuka Pharmaceutical Development & Commercialization, Inc.
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.

Overall Status Terminated
Start Date September 22, 2015
Completion Date July 24, 2017
Primary Completion Date July 24, 2017
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Change In Serum Sodium Concentration For Responders Day 2/2a, Day 4
Secondary Outcome
Measure Time Frame
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
Enrollment 9
Condition
Intervention

Intervention type: Drug

Intervention name: Tolvaptan

Other name: SAMSCA®

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

Gender: All

Minimum age: N/A

Maximum age: 17 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Global Clinical Development Study Director Otsuka Pharmaceutical Development & Commercialization, Inc.
Location
facility
| Aurora, Colorado, 80045, United States
| Washington, District of Columbia, 20010, United States
| New York, New York, 10032, United States
| Richmond, Virginia, 23298-0270, United States
| Seattle, Washington, 98105, United States
| Rome, 00165, Italy
| London, WC1N 3JH, United Kingdom
Location Countries

Italy

United Kingdom

United States

Verification Date

July 2018

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Tolvaptan Early Withdrawal

Arm group type: Experimental

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 group label: Tolvaptan Late Withdrawal

Arm group type: Experimental

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.

Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov