Effects of Tolvaptan vs Fluid Restriction in Hospitalized Subjects With Dilutional Hyponatremia
Condition: Hyponatremia; Dilutional Hyponatremia; Inappropriate ADH Syndrome
MeSH terms: Inappropriate ADH Syndrome; Hyponatremia
Intervention: tolvaptan; Fluid Restriction
Intervention description: 15 mg titrated to 30 mg then 60 mg once daily as oral tablet for up to 7 days based on response.; 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"
Intervention MeSH terms: Tolvaptan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 124.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hyponatremia; Dilutional Hyponatremia; Euvolemic Hyponatremia; Hypervolemic Hyponatremia; Fluid Restriction; Tolvaptan

Summary:

      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.
    

Eligibility criteria:

        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