An Extension Follow-up Trial to Evaluate the Long-term Safety of Children and Adolescent Participants With Euvolemic or Hypervolemic Hyponatremia

Study Overview
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Brief Summary
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The objective of this trial was to provide 6 months of safety follow-up for children and adolescents with dilutional (euvolemic or hypervolemic) hyponatremia who had previously participated in a tolvaptan hyponatremia trial and to assess the efficacy of tolvaptan in increasing serum sodium for those participants who received optional continuing tolvaptan treatment of variable duration (up to 6 months).

Detailed Description
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Core Safety Follow-up Component • For all participants: To evaluate the post-treatment safety follow-up of children and adolescent participants with dilutional (euvolemic or hypervolemic) hyponatremia who have previously participated in a tolvaptan hyponatremia trial. Optional Tolvaptan Treatment Component • For participants who receive optional tolvaptan treatment: To demonstrate that tolvaptan safely and effectively achieves and maintains increased serum sodium concentrations in children and adolescent participants with dilutional (euvolemic or hypervolemic) hyponatremia when used for both multiple short-term treatments, and/or longer chronic treatments.

Official Title
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A Phase 3b, Multicenter, Extension Follow-up Trial to Evaluate the Long-term Safety of Children and Adolescent Subjects With Euvolemic or Hypervolemic Hyponatremia Who Have Previously Participated in a Trial of Titrated Oral SAMSCA® (Tolvaptan)

Conditions
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Hyponatremia

Intervention / Treatment
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* Drug: Tolvaptan


Participation Criteria
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Eligibility Criteria
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Core Safety Follow-up Component Inclusion Criteria: Participation in a prior pediatric trial with tolvaptan for euvolemic or hypervolemic hyponatremia. Exclusion Criteria: None Optional Tolvaptan Treatment Component (per treatment cycle) Eligibility Criteria: Male and female participants ≥ 4 years of age (or per local Health Authority age restrictions) and ≥ 10 kilograms (kg). Participant must have been off treatment with the investigational medicinal product for at least 7 days following the end of treatment in the previous tolvaptan trial for hyponatremia (euvolemic or hypervolemic). Persistent dilutional (euvolemic or hypervolemic) hyponatremia defined as being documented as present for at least 48 hours, evidenced by at least 2 serum sodium assessments < 130 milliequivalents (mEq)/liter (L) (millimole [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 mEq/L (mmol/L), which will serve as the baseline value for efficacy endpoints, had to be obtained within 2 to 4 hours prior to the first dose of tolvaptan. Ability to swallow tablets. Ability to maintain adequate fluid intake whether orally or via intravenous 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 participant or local laws, prior to the initiation of any protocol-required procedures. In addition, the participant as required by local laws must provide informed assent at the pretreatment baseline for this trial 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 Institutional Review Board/Independent Ethics Committee and local regulatory requirements. Ability to commit to remain fully abstinent (periodic abstinence [for example, 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. Ineligibility Criteria: Had evidence of hypovolemia or intravascular volume depletion (for example, hypotension, clinical evidence of volume depletion, response to saline challenge); if the participant had systolic blood pressure or heart rate outside of the normal range for that age, then volume status was to be specifically clinically assessed to rule out volume depletion. Had serum sodium < 120 mEq/L (mmol/L), with or without associated neurologic impairment (that is, symptoms such as apathy, confusion, or seizures). Use of potent CYP3A4 inhibitors in participants ≤ 50 kg or moderate CYP3A4 inhibitors in participants < 20 kg. Lacked free access to water (inability to respond to thirst) or without ICU-level fluid monitoring and management. Had a history or current diagnosis of nephrotic syndrome. Had transient hyponatremia likely to resolve (for example, head trauma or post-operative state). Had hyperkalemia defined as serum potassium above the upper limit of normal (ULN) for the appropriate pediatric age range. Had estimated glomerular filtration rate (eGFR) < 30 milliliters (mL)/minute (min)/1.73 meters squared (m^2) calculated by the following equation: eGFR (mL/min/1.73 m^2) = 0.413 x height (centimeter [cm])/serum creatinine (mg/deciliter [dL]). Had acute kidney injury defined as: Increase in serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 micromoles [μmol]/L) within 48 hours; or increase in serum creatinine to ≥ 1.5 times baseline, which was known or presumed to have occurred within the prior 7 days; or urine volume < 0.5 mL/kg/hour for 6 hours. Had severe or acute neurological symptoms requiring other intervention (for example, hyperemesis, obtundation, seizures). Had had treatment for hyponatremia with: Hypertonic saline (including normal saline challenge) within 8 hours of qualifying sodium assessments; Urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of qualifying serum sodium assessments; Other treatment for the purpose of increasing serum sodium concurrent with dosing of trial medication Had anuria or urinary outflow obstruction, unless the participant was, or could be, catheterized during the trial. Had a history of drug or medication abuse within 3 months prior to the pretreatment visit or current alcohol abuse. Had a history of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives (such as benazepril). Had psychogenic polydipsia (participants with other psychiatric illness may be included per medical monitor approval). Had uncontrolled diabetes mellitus, defined as fasting glucose > 300 mg/dL (16.7 mEq/L [mmol/L]). Had screening liver function values > 3 x ULN. Had cirrhosis and met any of the following conditions: a major gastrointestinal bleed within the past 6 months, evidence of active bleeding (for example, epistaxis, petechiae/purpura, hematuria, or hematochezia), platelet count < 50,000/μL, or use of concomitant medications known to increase bleeding risk. Had hyponatremia due to the result of any medication that can safely be withdrawn (for example, thiazide diuretics). Had hyponatremia (for example, hyponatremia in the setting of adrenal insufficiency, untreated hypothyroidism, or hypotonic fluid administration) that is most appropriately corrected by alternative therapies. Was currently pregnant or breastfeeding. Had any medical condition that, in the opinion of the investigator, could interfere with evaluation of the trial objectives or safety of the participants. Was deemed unsuitable for trial participation in the opinion of the investigator. Participation in another investigational drug trial within the past 30 days, without prior approval from the sponsor medical monitor. Participants < 4 years of age (or per local Health Authority age restrictions), weight < 10 kg, or who were unable to swallow tablets.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tolvaptan<br>Participants enrolled in this trial were eligible to receive open-label tolvaptan if they had a clinical need as determined by the investigator and met the eligibility criteria for optional tolvaptan treatment. Daily dose levels would have included 3.75 milligrams (mg), 7.5 mg, 15 mg, 30 mg, and 60 mg. | Drug: Tolvaptan<br>* Tolvaptan 3.75-, 7.5-, 15-, and 30-mg spray-dried tablets. Dosage: Depending on age and weight, Tablet (3.75 mg - 60 mg daily). Frequency: Once daily. Duration: Participants may be eligible to receive short-term or long-term optional tolvaptan treatment at any time during their participation in the trial, with one or more treatment cycles over a 6-month period.<br>* Other names: SAMSCA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline At Month 6 In Serum Sodium While Tolvaptan Was Being Administered | No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure. | Baseline, Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Of Participants Who Required Rescue Therapy While On Tolvaptan Treatment | No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure. | Month 6 | 
| Percentage Of Participants Who Had Recurrence Of Hyponatremia While On Tolvaptan | No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure. | Month 6 | 
| Percentage Of Participants Requiring Continuation Of Tolvaptan Following 30 Days Of Treatment | No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure. | Month 6 | 
| Change From Baseline In Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale (GCS) Total Score At Month 6 | The PedsQL GCS was used for quality of life assessment. It is appropriate for at least 2 years of age, however availability may be limited for certain ages and languages. It encompasses 4 dimensions of functioning (physical, emotional, social, school). The age groups covered are: Toddler (2-4 years), Young child (5-7 years), Child (8-12 years), and Adolescent (13-18 years). Depending on the participant's age, the questionnaire may be completed by either the participant or the parent/caregiver, as appropriate. For the Toddler group, the PedsQL GCS consists of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consists of 23 items, with a 3-point Likert scale (0, 2, 4) for the Young Child, and a 5-point Likert scale for the Child and Adolescent groups. Scores are transformed on a scale from 0 to 100 and averaged. Higher scores indicate improved quality of life. The change from baseline in the GCS total score is presented. | Baseline, Month 6 | 
| Change From Baseline In PedsQL GCS Physical Health Summary Score At Month 6 | The PedsQL GCS was used for quality of life assessment. It is appropriate for at least 2 years of age, however availability may be limited for certain ages and languages. It encompasses 4 dimensions of functioning (physical, emotional, social, school). The age groups covered are: Toddler (2-4 years), Young child (5-7 years), Child (8-12 years), and Adolescent (13-18 years). Depending on the participant's age, the questionnaire may be completed by either the participant or the parent/caregiver, as appropriate. For the Toddler group, the PedsQL GCS consists of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consists of 23 items, with a 3-point Likert scale (0, 2, 4) for the Young Child, and a 5-point Likert scale for the Child and Adolescent groups. Scores are transformed on a scale from 0 to 100 and averaged. Higher scores indicate improved quality of life. The change from baseline in the physical health dimension is presented. | Baseline, Month 6 | 
| Change From Baseline In PedsQL GCS Psychosocial Health Summary Score At Month 6 | The PedsQL GCS was used for quality of life assessment. It is appropriate for at least 2 years of age, however availability may be limited for certain ages and languages. It encompasses 4 dimensions of functioning (physical, emotional, social, school). The age groups covered are: Toddler (2-4 years), Young child (5-7 years), Child (8-12 years), and Adolescent (13-18 years). Depending on the participant's age, the questionnaire may be completed by either the participant or the parent/caregiver, as appropriate. For the Toddler group, the PedsQL GCS consists of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consists of 23 items, with a 3-point Likert scale (0, 2, 4) for the Young Child, and a 5-point Likert scale for the Child and Adolescent groups. Scores are transformed on a scale from 0 to 100 and averaged. Higher scores indicate improved quality of life. The change from baseline in summed emotional, social, and school dimensions is presented. | Baseline, Month 6 | 
| Change From Baseline In PedsQL Multidimensional Fatigue Scale (MFS) Total Score At Month 6 | The PedsQL GCS was used for quality of life assessment. It is appropriate for at least 2 years of age, however availability may be limited for certain ages and languages. It encompasses 4 dimensions of functioning (physical, emotional, social, school). The age groups covered are: Toddler (2-4 years), Young child (5-7 years), Child (8-12 years), and Adolescent (13-18 years). Depending on the participant's age, the questionnaire may be completed by either the participant or the parent/caregiver, as appropriate. For the Toddler group, the PedsQL GCS consists of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consists of 23 items, with a 3-point Likert scale (0, 2, 4) for the Young Child, and a 5-point Likert scale for the Child and Adolescent groups. Scores are transformed on a scale from 0 to 100 and averaged. Higher scores indicate improved quality of life. The change from baseline in summed emotional, social, and school dimensions is presented. | Baseline, Month 6 | 
| Percentage Of Participants With Overly Rapid Correction In Serum Sodium 24 Hours After The First Dose At Introduction Or Reintroduction Of Tolvaptan | No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure. | Month 6 | 
| Plasma Concentrations Of Tolvaptan And Metabolites In Participants Who Had Continued Tolvaptan Therapy For Eight Consecutive Weeks | No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure. | 8 Weeks | 
| Participants With A Tanner Staging Score Of 1 At Month 6 | Tanner Staging assessment consists of 2 domains (pubic hair and breast development) for girls and 3 domains (pubic hair, penis development, and testes development) for boys. Staging was based on a single score summarizing the domains (not individual domain scores). Stages range from 1-5, with 1 indicating preadolescent and 5 adult. Participants with a Tanner staging score of 1 (preadolescent) at Month 6 are reported. | Month 6 | 
| Change From Baseline In Growth Percentiles For Body Height And Weight At Month 6 | Changes from baseline in growth percentiles for body height and weight were calculated and are reported. | Baseline, Month 6 | 
| Change From Baseline In Alanine Aminotransferase (ALT) And Aspartate Aminotransferase (AST) For Participants On Tolvaptan At Month 2 | No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected. Data reported only include assessments made for ALT and AST during the Core Safety Follow-up Component of the trial. Results are reported in units/liter (U/L). | Baseline, Month 2 | 
| Change From Baseline In Bilirubin For Participants On Tolvaptan At Month 2 | No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected. Data reported only include assessments made for bilirubin during the Core Safety Follow-up Component of the trial. Results are reported in micromoles (umol)/L. | Baseline, Month 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyponatremia, Euvolemic, Hypervolemic, Serum sodium, Dilutional hyponatremia, Electrolyte abnormality, Electrolyte imbalance, Metabolic disease, Water-Electrolyte Imbalance