Effects of Tolvaptan vs Fluid Restriction in Hospitalized Subjects With Dilutional Hyponatremia

Study Overview
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Brief Summary
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The purpose of this study is to determine if hospitalized patients with symptomatic hyponatremia treated with tolvaptan are in the hospital for less time than patients treated with fluid restriction. The study will also test if tolvaptan is better than fluid restriction in treating the symptoms of hyponatremia in hospitalized patients.

Official Title
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Phase 3b, Multicenter, Randomized, Single-blind, Parallel Group Trial of the Effects of Titrated Oral SAMSCA(r) (Tolvaptan) 15, 30, or 60 mg QD Compared to Placebo Plus Fluid Restriction on Length of Hospital Stay and Symptoms in Subjects Hospitalized With Dilutional Hyponatremia

Conditions
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Hyponatremia, Dilutional Hyponatremia, Inappropriate ADH Syndrome

Intervention / Treatment
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* Drug: tolvaptan
* Other: Fluid Restriction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hyponatremia in clinically euvolemic or hypervolemic states, defined as serum sodium < 130 mEq/L prior to randomization Clinically significant symptoms of hyponatremia, defined as a CGI-S score between 3-6, inclusive Female subjects of child bearing potential who agree to remain abstinent or to practice double-barrier forms of birth control from screening through 30 days following first dose on IMP Exclusion Criteria: Women who are pregnant or breast feeding, and females of childbearing potential who are not using acceptable contraceptive methods (such as barrier contraceptives or methods that result in a failure rate of less than 1%) Hyponatremia in hypovolemic states, defined as the presence of clinical and historical evidence of extracellular fluid volume depletion, including but not limited to skin turgor, orthostatic changes in blood pressure or heart rate, dry mucous membranes, or a response to IV saline challenge Subjects who are likely to require prolonged hospitalization for reasons other than hyponatremia, eg. new femoral fracture, surgeries requiring extended recovery Recent prior treatment for hyponatremia: hypertonic saline (including normal saline challenge) (within 8 hours of baseline) or urea, lithium, demeclocycline, conivaptan or tolvaptan (within 4 days of baseline). Includes any treatment, other than fluid restriction for the purpose of increasing serum sodium. Hyponatremia symptoms of a severity (eg, CGI = 7) such that they require immediate intervention with hypertonic saline; or are expected to require such therapy within 48 hours Causes of neurological symptoms which are attributable to psychological (psychosis), structural (dementia of the Alzheimer's type, stroke, transient ischemic attack, multi-infarct dementia) or other metabolic causes (eg. hyper- or hypo-: oxemia, glycemia, calcemia, ammonemia, etc) Acute and transient hyponatremia associated with head trauma or severe neurological injury (eg. stroke, subdural hematoma)or the use of recreational drugs. History of hyponatremia known to be due to severe, untreated hypothyroidism/adrenal insufficiency Subjects with psychogenic polydipsia Systolic arterial blood pressure < 90 mmHg at screening History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives (such as benazepril), or tolvaptan History of drug or medication abuse within the 3 months prior to screening, or current alcohol abuse Uncontrolled diabetes mellitus defined as glucose > 300 mg/dL [16.7 mmol/L] Current urinary tract obstruction (eg, obstructive benign prostatic hypertrophy) Current condition of anuria Serum creatinine > 3.5 mg/dL at screening Terminally ill or moribund condition with little chance of short-term (eg, 30 day) survival Subjects whose hyponatremia is the result of any medication that can safely be withdrawn (examples of drugs often not withdrawn include: anticonvulsants [eg, carbamazepine] and antipsychotics [eg, haloperidol]) Patients receiving DDAVP within 2 days of screening Patients with history of active variceal bleeding within the past 30 days, without prior approval from sponsor medical monitor Participation in another investigational drug trial within the past 30 days

Ages Eligible for Study
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Minimum 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tolvaptan 15-60mg<br>Oral tablet without fluid restriction. After the initial dose, daily dose may be titrated based on response. | Drug: tolvaptan<br>* 15 mg titrated to 30 mg then 60 mg once daily as oral tablet for up to 7 days based on response.<br>* Other names: OPC-156;|
| Active Comparator: Fluid Restriction<br>Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may titrated based response. | Other: Fluid Restriction<br>* Placebo tablet once daily with prescribed daily fluid intake of 1500 mL, then intensifying to 2 lower volumes of fluid intake for up to 7 days based on response. Since all particpants were blinded to treatment, titration to stricter fluid restriction followed the same algorithm as tolvaptan, increasing both the level of fluid restriction and increasing the placebo dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of Hospital Stay (LoS) | LoS was time to clinically ready to be hospital discharged (CRBD) from study treatment initiation, disregarding prolonged hospitalization due solely to social factors. | 45 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms. | Change from baseline in blinded rater assessed CGI-S at 48 hours post-first dose or at discharge/rescue therapy, if earlier was assessed. The CGI-S is a one-question rating scale which was as follows: Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time? 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients. | Baseline to 48 hours post dose | 
| Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. | Change in CGI-S of hyponatremia symptoms from pretreatment baseline at 24 and 72 hours post-first dose, or at discharge/rescue therapy if earlier was assessed. The CGI-S is a one-question rating scale which was as follows: Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time? 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients. | Baseline to 24 and 72 hours post dose | 
| Change From Baseline to 48 Hours Post Dose in Clinical Global Impression - Improvement (CGI-I) Score of Hyponatremia Symptoms. | Change in CGI-I score at 48 hours post-first dose or discharge/rescue therapy, if earlier was assessed. The CGI-I is a one-question rating scale where the participant is asked to rate total improvement whether or not, in their judgment, it is due entirely to trial treatment. Compared to his/her condition at admission to the trial, how much has he/she changed? 0=not assessed; 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse | Baseline to 48 hours post dose | 
| Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]). | Average 24 hour AUC of serum sodium concentration change from baseline, from Day 1 Hour 0 up to 72 hours post-first dose was assessed. A serum sodium sample was drawn at pre-treament and 8, 24, 48, and 72 hours post-first dose. Serum sodium was also assessed between 36 and 72 hours after the last dose. Analysis of AUC was for daily average AUC, hence the units or AUC are mEq/L/24 hours. | 0 to 72 hours | 
| Time to First 2-point Improvement in CGI-S Score. | CGI-S data up to 72 hours were used to identify 2-point improvements. Please refer to outcome measure 2 for details on the scale. For the analysis of time to first 2-point improvement in CGI-S, CGI-S data up to Hour 72 were used to identify 2-point improvements. Data for participants who received rescue therapy were censored at the time of receiving rescue therapy. For participants who were discharged before Hour 72 without reaching 2-point improvement in CGI-S, data were censored at the time of discharge. Other participants who did not reach the 2-point improvement during the 72 hours also had their data censored at their last CGI-S observations within 72 hours. | Up to 72 hours | 
| Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2. | Percentage of responders (defined as CGI-I score of 1 = very much improved or 2 = much improved) at 48 hours post-first dose, or at discharge/rescue therapy, if earlier. Participants given rescue therapy were given a score of 7. | 48 hours post dose | 
| Percentage of Participants Requiring Rescue Therapy for Hyponatremia | Percentage of participants requiring rescue therapy within first 7 days of treatment for hyponatremia. | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyponatremia, Dilutional Hyponatremia, Euvolemic Hyponatremia, Hypervolemic Hyponatremia, Fluid Restriction, Tolvaptan